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YAMASHITA Tomoya
Graduate School of Science, Technology and Innovation / Department of Science, Technology and Innovation
Professor

Researcher basic information

■ Research Keyword
  • Vascular biology
  • 腸内細菌
  • Immunology
  • Atherosclerosis
  • 循環器内科学
■ Research Areas
  • Life sciences / Internal medicine - General
  • Life sciences / Bacteriology
  • Life sciences / Cardiology

Research activity information

■ Award
  • Jul. 2016 日本動脈硬化学会, 五島雄一郎賞, Intestinal Immunity and Gut Microbiota in Atherogenesis.
    YAMASHITA TOMOYA
    Japan society

  • Apr. 2011 American Heart Association, 2011 Daniel Steinberg New Investigator Award in Atherosclerosis/Lipoproteins
    Yamashita Tomoya

■ Paper
  • Yuya Suzuki, Takuo Emoto, Shunsuke Sato, Takeshi Yoshida, Mitsuhiko Shoda, Hiromi Endoh, Manabu Nagao, Tomoyo Hamana, Taishi Inoue, Tomohiro Hayashi, Eriko Nitta, Hiroki Konishi, Kunihiko Kiuchi, Mitsuru Takami, Kimitake Imamura, Masayuki Taniguchi, Masatoshi Inoue, Toshihiro Nakamura, Yusuke Sonoda, Hiroyuki Takahara, Kazutaka Nakasone, Kyoko Yamamoto, Kenichi Tani, Hidehiro Iwai, Yusuke Nakanishi, Shogo Yonehara, Atsushi Murakami, Ryuji Toh, Takenao Ohkawa, Tomoyuki Furuyashiki, Ryo Nitta, Tomoya Yamashita, Ken-Ichi Hirata, Koji Fukuzawa
    Atrial fibrillation (AF) is strongly associated with strokes, heart failure, and increased mortality. This study aims to identify the monocyte-macrophage heterogeneity and interactions of these cells with non-immune cells, and to identify functional biomarkers in patients with AF. Therefore, we assess the single cell landscape of left atria (LA), using a combination of single cell and nucleus RNA-seq. Myeloid cells in LA tissue are categorized into five macrophage clusters, three monocyte clusters, and others. Cell-Chat analysis revealed that monocytes and IL1B+ macrophages send epidermal growth factor (EGF) signals to fibroblasts. Amphiregulin (AREG) is the most upregulated gene in monocytes and IL1B+ macrophages in the AF group, compared with healthy controls from other groups. Serum AREG levels are higher in patients with persistent AF. These data suggested that EGF signaling pathway could be a therapeutic target for AF and serum AREG levels provide an effective biomarker for predicting persistent AF.
    Dec. 2024, Communications biology, 7(1) (1), 1601 - 1601, English, International magazine
    Scientific journal

  • Masato Ogawa, Seimi Satomi-Kobayashi, Naofumi Yoshida, Kodai Komaki, Takumi Hirabayashi, Kumiko Wakida, Saori Saitoh, Takeshi Inoue, Tomoya Yamashita, Yoshitada Sakai, Michiko Takahashi, Kenji Okada, Ken-ichi Hirata
    Elsevier BV, Dec. 2024, Clinical Nutrition
    Scientific journal

  • Yuji Kanejima, Masato Ogawa, Kodai Ishihara, Naofumi Yoshida, Michikazu Nakai, Koshiro Kanaoka, Yoko Sumita, Takuo Emoto, Yoshitada Sakai, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Tomoya Yamashita, Kenichi Hirata, Kazuhiro P Izawa
    BACKGROUND: Body mass index (BMI) of patients with ischemic stroke (IS) has been associated with prognosis and disability in studies in the United States. Although the Asian population is leaner, the optimal BMI for stroke-related disability remains unknown. OBJECTIVES: To clarify the association between BMI and disability in patients with IS from a national database in Japan. METHODS: The present study included 522,421 patients with IS identified in the JROAD-DPC database from April 2016 to March 2020. We used the WHO classification of BMI, which divides Asia-Pacific patients into five groups, to categorize BMI and the modified Rankin Scale (mRS) to assess stroke-related disability at admission and discharge. After multiple imputation for missing values, we conducted a multiple mixed-effect logistic regression analysis for poor mRS score (>2) in September 2023. In addition, we created a restricted cubic spline model between the odds ratio (OR) for poor mRS and BMI. RESULTS: The mRS score worsened during hospitalization in 60.1% of the patients with IS, and 45.7% had a poor mRS score at discharge. Overweight patients had the lowest OR of having a poor mRS score (OR: 0.898, 95% confidence interval: 0.895-0.902). The spline curve for the OR for poor mRS score was U-shaped with a BMI of 24.7 kg/m2as the apex value. CONCLUSION: The present study revealed a U-shaped relationship between BMI and stroke-related disability, with overweight patients having the lowest OR for disability at discharge.
    Oct. 2024, Topics in stroke rehabilitation, 1 - 10, English, International magazine
    Scientific journal

  • Yuji Kanejima, Masato Ogawa, Kodai Ishihara, Naofumi Yoshida, Michikazu Nakai, Koshiro Kanaoka, Yoko Sumita, Takuo Emoto, Yoshitada Sakai, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Tomoya Yamashita, Kenichi Hirata, Kazuhiro P. Izawa
    ABSTRACT BACKGROUND Intracerebral hemorrhage (ICH) has a high mortality rate, and even if patients survive, they are likely to have severe disability. Body mass index (BMI) is associated with ICH risk, and extremely low and high BMIs are associated with the site of ICH, which affects functional decline. However, few reports exist on ICH-related functional decline and BMI. This study aimed to clarify the relationship between BMI and stroke-related disability of patients with ICH. METHODS Patients with ICH registered in the Japanese Registry Of All Cardiac and Vascular Diseases Diagnosis Procedure Combination (JROAD-DPC) database from April 2016 to March 2020 were included. BMI was defined according to the World Health Organization Asia-Pacific classification. Functional disability was assessed using the modified Rankin Scale (mRS). ICH-related functional decline was defined as an increase in mRS score at discharge compared with that of the pre-stroke assessment. RESULTS This study included 155,211 patients with ICH whose median age was 72.0 years and mean BMI was 22.3 kg/m2. The ratio of patients with ICH who experience functional decline was 74.9%. The spline curve between BMI and ICH-related functional decline was U-shaped, revealing that the Normal to Obese I BMI groups (BMI: 22.2–30.4 kg/m2) exhibited reduced odds ratios for ICH-related functional decline. Hospitalization cost and BMI showed similar U-shaped patterns, with a BMI of 25.0 kg/m2as the lowest point, regardless of age group. CONCLUSION In patients with ICH, those with both extremely low and high BMIs were more likely to experience functional decline after ICH onset, which resulted in increased hospitalization costs. To reduce ICH-related functional decline, patients should be managed at a normal to slightly obese BMI.
    Cold Spring Harbor Laboratory, Jul. 2024

  • Taishi Inoue, Takuo Emoto, Katsuhiro Yamanaka, Shunya Chomei, Shunsuke Miyahara, Hiroaki Takahashi, Ryohei Shinohara, Takeshi Kondo, Masayuki Taniguchi, Tomoyuki Furuyashiki, Tomoya Yamashita, Ken-Ichi Hirata, Kenji Okada
    There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B+ inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B+ inflammatory macrophages differentiated from S100A8/9/12+ classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.
    Jun. 2024, Scientific reports, 14(1) (1), 14893 - 14893, English, International magazine
    Scientific journal

  • Shintaro Takeda, Takuo Emoto, Tomoya Yamashita, Hiroyuki Yamamoto, Tomofumi Takaya, Takahiro Sawada, Takeshi Yoshida, Masatoshi Inoue, Yuya Suzuki, Tomoyo Hamana, Taishi Inoue, Masayuki Taniguchi, Naoto Sasaki, Hiromasa Otake, Takenao Ohkawa, Tomoyuki Furuyashiki, Hiroya Kawai, Ken-Ichi Hirata
    BACKGROUND: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS. METHODS: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45+ immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis. RESULTS: CD4+ T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7+ (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3)+ regulatory CD4+ T cells. The proportion of central memory CD4+ T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4+ T cells into effector CD4+ T cells and that from naive CD4+ T cells into central memory CD4+ T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4+ T cells. CONCLUSIONS: For the first time, we revealed single cell-level characteristics of CD4+ T cells in patients with ACS. CD4+ T cells could be therapeutic targets of ACS. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN000040747.
    May 2024, Arteriosclerosis, thrombosis, and vascular biology, 44(5) (5), 1135 - 1143, English, International magazine
    [Refereed]
    Scientific journal

  • Satoshi WATANABE, Naofumi YOSHIDA, Kairi BABA, Hiroyuki YAMASAKI, Natsuko O. SHINOZAKI, Masato OGAWA, Tomoya YAMASHITA, Aya K. TAKEDA
    BMFH Press, 2024, Bioscience of Microbiota, Food and Health, 43(1) (1), 64 - 72
    [Refereed]
    Scientific journal

  • Sayo Horibe, Takuo Emoto, Taiji Mizoguchi, Toru Tanaka, Shoji Kawauchi, Naoto Sasaki, Tomoya Yamashita, Koji Ikeda, Noriaki Emoto, Ken‐ichi Hirata, Yoshiyuki Rikitake
    Abstract Alzheimer's disease (AD) is among the most prevalent age‐related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter‐driven dominant negative telomeric repeat‐binding factor 2 transgenic mice (TERF2DN‐Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid‐β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild‐type mice, microglia in TERF2DN‐Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single‐cell RNA‐sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease‐associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.
    Wiley, Aug. 2023, Glia
    [Refereed]
    Scientific journal

  • Hiroyuki Yamamoto, Tomofumi Takaya, Takuo Emoto, Shintaro Takeda, Naofumi Yoshida, Takahiro Sawada, Tomoya Yamashita, Ken-ichi Hirata, Hiroya Kawai
    Japanese Society of Internal Medicine, Feb. 2023, Internal Medicine, 62(3) (3), 399 - 403
    [Refereed]
    Scientific journal

  • Ryohei Shinohara, Hitomi Nakashima, Takuo Emoto, Tomoya Yamashita, Yoshihiro Saito, Naofumi Yoshida, Taishi Inoue, Katsuhiro Yamanaka, Kenji Okada, Ken-ichi Hirata
    Background: Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease characterized by dilated abdominal aorta. Immune cells have been shown to contribute to the development of AAA, and that the gut microbiota is associated with numerous diseases, including cardiovascular diseases, by regulating immune systems or metabolic pathways of the host. However, the interaction between the gut microbiota and AAA remains unknown. Methods: Apolipoprotein E–deficient male mice were fed a high-cholesterol diet and divided into three groups: the control group was maintained under normal water (control group), the oral AVNM group was maintained under drinking water supplemented with ampicillin, vancomycin, neomycin, and metronidazole, and the i.p. AVNM group was injected AVNM intraperitoneally. After 1 week of pretreatment with antibiotics, these mice were administrated Ang II via subcutaneous osmotic pumps for 4 weeks and euthanized to evaluate AAA formation. Results: Depletion of gut microbiota by oral AVNM ameliorated the incidence of AAAs (control group: 58.9% versus oral AVNM group: 28.6% versus i.p. AVNM group: 75.0%, P = 0.0005) and prevented death due to ruptured aneurysms (control group: 11% versus oral AVNM group: 0% versus i.p. AVNM group: 15%). Oral AVNM suppressed monocyte storage in the spleen, but not in other organs. Despite possessing a higher level of cholesterol, recruitment of monocytes into the suprarenal aorta was suppressed in the oral AVNM group. In AVNM drinking mice, NOD1 ligand, a kind of PRR ligands, increased the development of AAAs and accumulation of macrophages in the aortae. Conclusions: The gut microbiota plays a critical role in AAA formation. Therefore, regulation of the microbiota or the immune system can be a therapeutic approach for AAA.
    Ovid Technologies (Wolters Kluwer Health), Dec. 2022, Hypertension, 79(12) (12), 2821 - 2829
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Masato Ogawa, Michikazu Nakai, Koshiro Kanaoka, Yoko Sumita, Takuo Emoto, Yoshihiro Saito, Hiroyuki Yamamoto, Kazuhiro P. Izawa, Yoshitada Sakai, Yushi Hirota, Wataru Ogawa, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Tomoya Yamashita, Ken-ichi Hirata
    Abstract Body mass index (BMI) distribution and its impact on cardiovascular disease (CVD) vary between Asian and western populations. The study aimed to reveal time-related trends in the prevalence of obesity and underweight and safe ranges of BMI in Japanese patients with CVD. We analyzed 5,020,464 records from the national Japanese Registry of All Cardiac and Vascular Diseases—Diagnosis Procedure Combination dataset over time (2012–2019) and evaluated BMI trends and the impact on in-hospital mortality for six acute CVDs: acute heart failure (AHF), acute myocardial infarction (AMI), acute aortic dissection (AAD), ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Patients were categorized into five groups using the WHO Asian-BMI criteria: underweight (< 18.5 kg/m2), normal (18.5–22.9 kg/m2), overweight at risk (23.0–24.9 kg/m2), obese I (25.0–29.9 kg/m2), and obese II (≥ 30.0 kg/m2). Age was significantly and inversely related to high BMI for all diseases (P < 0.001). The proportion of BMI categories significantly altered over time; annual BMI trends showed a significant and gradual increase, except AAD. In adjusted mixed models, underweight was significantly associated with a high risk of in-hospital mortality in all CVD patients (AHF, OR 1.41, 95% CI 1.35–1.48, P < 0.001; AMI, OR 1.27, 95% CI 1.20–1.35, P < 0.001; AAD, OR 1.23, 95% CI 1.16–1.32, P < 0.001; IS, OR 1.45, 95% CI 1.41–1.50, P < 0.001; ICH, OR 1.18, 95% CI 1.13–1.22, P < 0.001; SAH, OR 1.17, 95% CI 1.10–1.26, P < 0.001). Moreover, obese I and II groups were significantly associated with a higher incidence of in-hospital mortality, except AHF and IS. Age was associated with in-hospital mortality for all BMI categories in six CVD patients. BMI increased annually in patients with six types of CVDs. Although underweight BMI was associated with high mortality rates, the impact of obesity on in-hospital mortality differs among CVD types.
    Corresponding, Springer Science and Business Media LLC, Nov. 2022, Scientific Reports, 12(1) (1)
    [Refereed]
    Scientific journal

  • Masato Ogawa, Naofumi Yoshida, Michikazu Nakai, Koshiro Kanaoka, Yoko Sumita, Yuji Kanejima, Takuo Emoto, Yoshihiro Saito, Hiroyuki Yamamoto, Yoshitada Sakai, Yushi Hirota, Wataru Ogawa, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Tomoya Yamashita, Kazuhiro P. Izawa, Ken-ichi Hirata
    Elsevier BV, Nov. 2022, International Journal of Cardiology, 367, 38 - 44
    [Refereed]
    Scientific journal

  • Yoshihiro Saito, Tomoya Yamashita, Naofumi Yoshida, Takuo Emoto, Shintaro Takeda, Tokiko Tabata, Masakazu Shinohara, Shigenobu Kishino, Yuta Sugiyama, Nahoko Kitamura, Hiroyuki Yamamoto, Tomofumi Takaya, Jun Ogawa, Ken-ichi Hirata
    Corresponding, Elsevier BV, Oct. 2022, Atherosclerosis, 358, 1 - 11
    [Refereed]
    Scientific journal

  • Kazuyuki Kasahara, Naoto Sasaki, Hilman Zulkifli Amin, Toru Tanaka, Sayo Horibe, Tomoya Yamashita, Ken-Ichi Hirata, Yoshiyuki Rikitake
    Compelling evidence suggests a crucial role for Foxp3+ regulatory T cells (Tregs) in the control of atherosclerosis. Although suppression of pro-inflammatory CD4+ T cell immune responses is supposed to be important for athero-protective action of Foxp3+ Tregs, few studies have provided direct evidence for this protective mechanism. We investigated the impact of Foxp3+ Treg depletion on CD4+ T cell immune responses and the development of atherosclerosis under hypercholesterolemia. We employed DEREG (depletion of regulatory T cells) mice on an atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr -/-) background, which carry a diphtheria toxin (DT) receptor under the control of the foxp3 gene locus. In these mice, DT injection led to efficient depletion of Foxp3+ Tregs in spleen, lymph nodes and aorta. Depletion of Foxp3+ Tregs augmented CD4+ effector T cell immune responses and aggravated atherosclerosis without affecting plasma lipid profile. Notably, the proportion of pro-inflammatory IFN-γ-producing T cells were increased in spleen and aorta following Foxp3+ Treg depletion, implying that Foxp3+ Tregs efficiently regulate systemic and aortic T cell-mediated inflammatory responses under hypercholesterolemia. Unexpectedly, Foxp3+ Treg depletion resulted in an increase in anti-inflammatory IL-10-producing T cells, which was not sufficient to suppress the augmented proinflammatory T cell immune responses caused by reduced numbers of Foxp3+ Tregs. Our data indicate that Foxp3+ Tregs suppress pro-inflammatory CD4+ T cell immune responses to control atherosclerosis under hypercholesterolemia.
    Jul. 2022, Heliyon, 8(7) (7), e09981, English, International magazine
    [Refereed]
    Scientific journal

  • Takuo Emoto, Hiroyuki Yamamoto, Tomoya Yamashita, Tomofumi Takaya, Takahiro Sawada, Shintaro Takeda, Masayuki Taniguchi, Naoto Sasaki, Naofumi Yoshida, Yoshihiro Saito, Tharini Sivasubramaniyam, Hiromasa Otake, Tomoyuki Furuyashiki, Clinton S Robbins, Hiroya Kawai, Ken-Ichi Hirata
    Corresponding, May 2022, Circulation, 145(18) (18), 1434 - 1436, English, International magazine
    [Refereed]

  • TAKEHIRO OTOSHI, TATSUYA NAGANO, JONGUK PARK, KOJI HOSOMI, TOMOYA YAMASHITA, MOTOKO TACHIHARA, TOKIKO TABATA, REINA SEKIYA, YUGO TANAKA, KAZUYUKI KOBAYASHI, KENJI MIZUGUCHI, TOMOO ITOH, YOSHIMASA MANIWA, JUN KUNISAWA, YOSHIHIRO NISHIMURA
    Anticancer Research USA Inc., Mar. 2022, Anticancer Research, 42(3) (3), 1589 - 1598
    [Refereed]
    Scientific journal

  • Naoki Saji, Yoshihiro Saito, Tomoya Yamashita, Kenta Murotani, Tsuyoshi Tsuduki, Takayoshi Hisada, Taiki Sugimoto, Shumpei Niida, Kenji Toba, Takashi Sakurai
    BACKGROUND: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and lipopolysaccharides (LPS; molecules of the outer membrane of gram-negative bacteria) remain controversial. OBJECTIVE: To evaluate associations between plasma LPS, gut microbiota, and cognitive function. METHODS: We performed a cross-sectional sub-analysis of data of 127 participants (women: 58%, mean age: 76 years) from our prospective cohort study regarding the relationship between gut microbiota and cognitive function. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites. We evaluated relationships between cognitive decline and plasma LPS using multivariable logistic regression analyses. RESULTS: Plasma LPS concentration increased with increasing degree of cognitive decline and total cerebral small vessel disease (SVD) score (Kruskal-Wallis test; p = 0.016 and 0.007, respectively). Participants with high plasma LPS concentrations tended to have lower concentrations of gut microbial metabolites, such as lactic acid and acetic acid, and were less likely to consume fish and shellfish (44.7% versus 69.6%, p = 0.027) than those with low plasma LPS concentrations. Multivariable analyses revealed that plasma LPS concentration was independently associated with the presence of mild cognitive impairment in participants without dementia (odds ratio: 2.09, 95% confidence interval: 1.14-3.84, p = 0.007). CONCLUSION: In this preliminary study, plasma LPS concentration was associated with both cognitive decline and cerebral SVD and significantly correlated with beneficial gut microbial metabolites. Plasma LPS may be a risk factor for cognitive decline.
    2022, Journal of Alzheimer's disease : JAD, 86(4) (4), 1947 - 1957, English, International magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Satoshi Watanabe, Hiroyuki Yamasaki, Hajime Sakuma, Aya K Takeda, Tomoya Yamashita, Ken-Ichi Hirata
    Imbalance of the gut microbiota plays an important role in the pathogenesis of various diseases. Although many clinical studies have analyzed the gut microbiota, the definition of normal gut microbiota remains unclear. In this study, we aim to establish the average gut microbiota in the healthy Japanese population. Using 16S ribosomal RNA gene sequencing, we analyzed gut microbial data from fecal samples obtained from 6,101 healthy Japanese individuals. Based on their ages, the individuals were divided into three groups: young, middle-age, and old. Individuals were further categorized according to body mass index (BMI) into lean, normal, and obese groups. The α and β diversities in the old group were significantly higher than those in the young and middle-age groups. The Firmicutes/Bacteroidetes ratio of subjects in the obese category was significantly lower compared with those of subjects in the lean and normal categories in the young and middle-age groups. Genus Bacteroides was the dominant gut microbiota across all the BMI categories in all the age groups. Among the top ten genera, the abundances of Bacteroides, Bifidobacterium, Anaerostipes, Blautia, Dorea, Fusicatenibacter, Lachnoclostridium, and Parabacteroides were significantly lower in the old group than in the young and middle-age groups. The correlation network at the genus level revealed different microbe-microbe interactions associated with age and BMI. We determined the average Japanese gut microbiota, and this information could be used as a reference. The gut microbiota greatly differs based on the life stage and metabolic status of the host, and this gives rise to a variety of host-gut microbe interactions that can lead to an increased susceptibility to disease.
    2022, Bioscience of microbiota, food and health, 41(2) (2), 45 - 53, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Tomoya Yamashita, Tatsunori Osone, Tetsuya Hosooka, Masakazu Shinohara, Seiichi Kitahama, Kengo Sasaki, Daisuke Sasaki, Takeshi Yoneshiro, Tomohiro Suzuki, Takuo Emoto, Yoshihiro Saito, Genki Ozawa, Yushi Hirota, Yasuyuki Kitaura, Yoshiharu Shimomura, Yuko Okamatsu-Ogura, Masayuki Saito, Akihiko Kondo, Shingo Kajimura, Takeshi Inagaki, Wataru Ogawa, Takuji Yamada, Ken-Ichi Hirata
    The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with Bacteroides dorei and Bacteroides vulgatus exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that Bacteroides probiotics could be used for treating obesity.
    Corresponding, Nov. 2021, iScience, 24(11) (11), 103342 - 103342, English, International magazine
    [Refereed]
    Scientific journal

  • Takuo Emoto, Tomohiro Hayashi, Tokiko Tabata, Tomoya Yamashita, Hikaru Watanabe, Tomoya Takahashi, Yasuhiro Gotoh, Kenjiro Kami, Naofumi Yoshida, Yoshihiro Saito, Hidekazu Tanaka, Kensuke Matsumoto, Tetsuya Hayashi, Takuji Yamada, Ken-Ichi Hirata
    BACKGROUND: We had previously reported an increase in trimethylamine N-oxide (TMAO) levels in patients with both compensated and decompensated heart failure (HF) and alteration in gut microbiota composition using 16S rRNA gene amplicon analysis. Although a metagenome-wide analysis showed that choline-TMA lyase levels increased in HF patients, which TMA generation pathway from choline, carnitine, or betaine contributes to the increase in TMAO levels in HF needs to be elucidated. METHODS: We conducted a metagenome-wide shotgun sequencing analysis of gut microbiota and measured the TMAO levels in plasma of 22 HF patients during the compensated phase and 11 age-, sex-, and comorbidity-matched control subjects, whose gut microbiota compositions were reported in a previous 16S rRNA-based analysis. RESULTS: The abundance of cntA/B was positively correlated with TMAO, especially in HF patients, whereas that of cutC/D or betaine reductase was not correlated either in controls or HF patients. The abundance of cntA/B was mainly derived from the genera Escherichia and Klebsiella either in controls or HF patients. CONCLUSION: TMAO levels in plasma depend on the abundance of cntA/B in HF. Although it is difficult to exclude the involvement of confounding factors, microbial dysbiosis connecting the abundance of cntA/B in the gut and the increase of TMAO in plasma can be a therapeutic target for HF.
    Corresponding, Sep. 2021, International journal of cardiology, 338, 138 - 142, English, International magazine
    [Refereed]
    Scientific journal

  • Kodai Komaki, Naofumi Yoshida, Seimi Satomi-Kobayashi, Yasunori Tsuboi, Masato Ogawa, Kumiko Wakida, Takayoshi Toba, Hiroyuki Kawamori, Hiromasa Otake, Atsushi Omura, Katsuhiro Yamanaka, Takeshi Inoue, Tomoya Yamashita, Yoshitada Sakai, Kazuhiro P Izawa, Kenji Okada, Ken-Ichi Hirata
    Assessment of frailty is important for risk stratification among the elderly with severe aortic stenosis (AS) when considering interventions such as surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). However, evidence of the impact of preoperative frailty on short-term postoperative outcomes or functional recovery is limited. This retrospective study included 234 consecutive patients with severe AS who underwent SAVR or TAVR at Kobe University Hospital between Dec 2013 and Dec 2019. Primary outcomes were postoperative complications, postoperative 6-min walking distance (6MWD), and home discharge rates. The mean age was 82 ± 6.6 years. There were 169 (SAVR: 80, TAVR: 89) and 65 (SAVR: 20, TAVR: 45) patients in the non-frail and frail groups, respectively (p = 0.02). The postoperative complication rates in the frail group were significantly higher than those in the non-frail group [30.8% (SAVR: 35.0%, TAVR: 28.9%) vs. 10.7% (SAVR: 15.0%, TAVR: 6.7%), p < 0.001]. The home discharge rate in the non-frail group was significantly higher than that in the frail group [85.2% (SAVR: 81.2%, TAVR: 88.8%) vs. 49.2% (SAVR: 55.0%, TAVR: 46.7%), p < 0.001]. The postoperative 6MWD in the non-frail group was significantly longer than that in the frail group [299.3 ± 87.8 m (SAVR: 321.9 ± 90.8 m, TAVR: 281.1 ± 81.3 m) vs. 141.9 ± 92.4 m (SAVR: 167.8 ± 92.5 m, TAVR: 131.6 ± 91.3 m), p < 0.001]. The TAVR group did not show a decrease in the 6MWD after intervention, regardless of frailty. We report for the first time that preoperative frailty was strongly associated with postoperative complications, 6MWD, and home discharge rates following both SAVR and TAVR. Preoperative frailty assessment may provide useful indications for planning better individualized therapeutic interventions and supporting comprehensive intensive care before and after interventions.
    Aug. 2021, Heart and vessels, 36(8) (8), 1234 - 1245, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Sachiyo Iwata, Masato Ogawa, Kazuhiro P Izawa, Shunsuke Kuroda, Shun Kohsaka, Taishi Yonetsu, Takeshi Kitai, Sho Torii, Takahide Sano, Yoshitada Sakai, Tomoya Yamashita, Ken-Ichi Hirata, Yuya Matsue, Shingo Matsumoto, Koichi Node
    Background: The COVID-19 pandemic has challenged healthcare systems, at times overwhelming intensive care units (ICUs). We aimed to describe the length and rate of ICU admission, and explore the clinical variables influencing ICU use, for COVID-19 patients with known cardiovascular diseases or their risk factors (CVDRF). Methods and Results: A post hoc analysis was performed of 693 Japanese COVID-19 patients with CVDRF enrolled in the nationwide CLAVIS-COVID registration system between January and May 2020 (mean [±SD] age 68.3±14.9 years; 35% female); 199 patients (28.7%) required ICU management. The mean (±SD) ICU length of stay (LOS) was 19.3±18.5 days, and the rate of in-hospital death and hospital LOS were significantly higher (P<0.001) and longer (P<0.001), respectively, in the ICU than non-ICU group. Logistic regression analysis revealed that clinical variables reflecting impaired general condition (e.g., high C-reactive protein, low Glasgow Coma Scale score, SpO2, albumin level), male sex, and previous use of β-blockers) were associated with ICU admission (all P<0.001). Notably, age was inversely associated with ICU admission, and this was particularly prominent among elderly patients (OR 0.97, 95% confidence interval 0.95-0.99; P=0.0018). Conclusions: One-third of COVID patients with CVDRF required ICU care during the first phase of the pandemic in Japan. Other than anticipated clinical variables, such as hypoxia and altered mental status, age was inversely associated with the use of the ICU, warranting further investigation.
    Jul. 2021, Circulation reports, 3(7) (7), 375 - 380, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Tomoya Yamashita, Naofumi Yoshida, Takuo Emoto, Yoshihiro Saito, Ken-Ichi Hirata
    Cardiovascular diseases (CVDs) have become a major health problem because of the associated high morbidity and mortality rates observed in affected patients. Gut microbiota has recently been implicated as a novel endocrine organ that plays critical roles in the regulation of cardiometabolic and renal functions of the host via the production of bioactive metabolites. This review investigated the evidence from several clinical and experimental studies that indicated an association between the gut microbiota-derived toxins and CVDs. We mainly focused on the pro-inflammatory gut microbiota-derived toxins, namely lipopolysaccharides, derived from Gram-negative bacteria, and trimethylamine N-oxide and described the present status of research in association with these toxins, including our previous research findings. Several clinical studies aimed at exploring the effectiveness of reducing the levels of these toxins to inhibit cardiovascular events are currently under investigation or in the planning stages. We believe that some of the methods discussed in this review to eliminate or reduce the levels of such toxins in the body could be clinically applied to prevent CVDs in the near future.
    Corresponding, Apr. 2021, Toxins, 13(5) (5), English, International magazine
    [Refereed]
    Scientific journal

  • Tomoya Yamashita, Naofumi Yoshida, Takuo Emoto, Ken-Ichi Hirata
    Apr. 2021, Journal of atherosclerosis and thrombosis, 28(4) (4), 314 - 316, English, Domestic magazine
    Scientific journal

  • Hideya Suehiro, Kunihiko Kiuchi, Koji Fukuzawa, Naofumi Yoshida, Mitsuru Takami, Yoshiaki Watanabe, Yu Izawa, Tomomi Akita, Makoto Takemoto, Jun Sakai, Toshihiro Nakamura, Atsusuke Yatomi, Hiroyuki Takahara, Yusuke Sonoda, Kazutaka Nakasone, Kyoko Yamamoto, Tomoya Yamashita, Ken-Ichi Hirata
    BACKGROUND: Inflammation, such as that associated with intermediate CD14++ CD16+ monocytes and atrial structural remodeling (SRM), may be important in the recurrence of atrial fibrillation (AF) after catheter ablation. However, the relationship between the intermediate CD14++ CD16+ monocytes, SRM, and AF recurrence is unclear. METHODS: Twenty-four patients with AF were enrolled. The proportion of intermediate monocytes (PIM) was assessed before ablation by flow cytometry. As a surrogate marker of SRM, the volume ratio (VR) of signal intensity greater than 1 standard deviation on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) was calculated. We investigated whether PIM correlated with SRM on LGE-MRI and determined the optimal cutoff value for predicting AF recurrence. RESULTS: Univariate analysis revealed positive correlations between PIM and BNP with SRM (PIM: r = .593, p = .002; BNP: r = .567, p = .004). Multivariable analysis revealed that PIM was independently associated with VR on LGE-MRI (β = .522; p = .033). The finding of an area under the receiver operating characteristic curve of 0.750 revealed that a VR ≥ 13.3% on LGE-MRI as the optimal cutoff value to predict AF recurrence with 80% sensitivity and 71% specificity, which was associated with PIM ≥ 10.0%. CONCLUSION: Intermediate monocytes were significantly positively correlated with SRM. PIM ≥ 10% was associated with a VR ≥ 13.3% on LGE-MRI, which predicted AF recurrence after catheter ablation.
    Apr. 2021, Journal of cardiovascular electrophysiology, 32(4) (4), 1035 - 1043, English, International magazine
    [Refereed]
    Scientific journal

  • Tomohiro Hayashi, Tomoya Yamashita, Tomoya Takahashi, Tokiko Tabata, Hikaru Watanabe, Yasuhiro Gotoh, Masakazu Shinohara, Kenjiro Kami, Hidekazu Tanaka, Kensuke Matsumoto, Tetsuya Hayashi, Takuji Yamada, Ken-Ichi Hirata
    Aims: Circulating amino acid (AA) abnormalities serve as predictors of adverse outcomes in patients with heart failure (HF). However, the role of the gut microbiota in AA disturbances remains unknown. Thus, we investigated gut microbial functions and their associations with AA metabolic alterations in patients with HF. Methods and Results: We performed whole-genome shotgun sequencing of fecal samples and mass spectrometry-based profiling of AAs in patients with compensated HF. Plasma levels of total essential AAs (EAAs) and histidine were significantly lower in patients with HF than in control subjects. HF patients also displayed increased and decreased abundance of gut microbial genes involved in the degradation and biosynthesis, respectively, of EAAs, including branched-chain AAs (BCAAs) and histidine. Importantly, a significant positive correlation was observed between the abundance of microbial genes involved in BCAA biosynthesis and plasma BCAA levels in patients with HF, but not in controls. Moreover, network analysis revealed that the depletion of Eubacterium and Prevotella, which harbor genes for BCAA and histidine biosynthesis, contributed to decreased abundance of microbial genes involved in the biosynthesis of those EAAs in patients with HF. Conclusions: The present study demonstrated the relationship between gut microbiota and AA metabolic disturbances in patients with HF.
    Corresponding, 2021, Frontiers in cardiovascular medicine, 8, 789325 - 789325, English, International magazine
    [Refereed]
    Scientific journal

  • Tokiko Tabata, Tomoya Yamashita, Koji Hosomi, Jonguk Park, Tomohiro Hayashi, Naofumi Yoshida, Yoshihiro Saito, Koji Fukuzawa, Kana Konishi, Haruka Murakami, Hitoshi Kawashima, Kenji Mizuguchi, Motohiko Miyachi, Jun Kunisawa, Ken-Ichi Hirata
    Atrial fibrillation (AF) reduces the quality of life by triggering stroke and heart failure. The association between AF onset and gut metabolites suggests a causal relationship between AF and gut microbiota dysbiosis; however, the relationship remains poorly understood. We prospectively enrolled 34 hospitalized patients with AF and 66 age-, sex-, and comorbidity-matched control subjects without a history of AF. Gut microbial compositions were evaluated by amplicon sequencing targeting the 16S ribosomal RNA gene. We assessed differences in dietary habits by using a brief-type self-administered diet history questionnaire (BDHQ). Gut microbial richness was lower in AF patients, although the diversity of gut microbiota did not differ between the two groups. At the genus level, Enterobacter was depleted, while Parabacteroides, Lachnoclostridium, Streptococcus, and Alistipes were enriched in AF patients compared to control subjects. The BDHQ revealed that the intake of n-3 polyunsaturated fatty acids and eicosadienoic acid was higher in AF patients. Our results suggested that AF patients had altered gut microbial composition in connection with dietary habits.
    Corresponding, Jan. 2021, Heart and vessels, 36(1) (1), 105 - 114, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Seiichi Kitahama, Tomoya Yamashita, Yasuko Hirono, Tokiko Tabata, Yoshihiro Saito, Ryohei Shinohara, Hitomi Nakashima, Takuo Emoto, Yushi Hirota, Tetsuya Takahashi, Wataru Ogawa, Ken-Ichi Hirata
    Laparoscopic sleeve gastrectomy (LSG) is an important therapeutic option for morbidly obese patients. Although LSG promotes sufficient weight loss, how LSG changes plasma metabolites remains unclear. We assessed changes in plasma metabolite levels after LSG. We collected plasma samples from 15 morbidly obese Japanese patients before and 3 months after LSG. A total of 48 metabolites were quantified using capillary electrophoresis time-of-flight mass spectrometry-based metabolomic profiling. Branched chain amino acids, several essential amino acids, choline, 2-hydroxybutyric acid, 2-oxoisovaleric acid and hypoxanthine were significantly decreased after LSG. Tricarboxylic acid cycle metabolites, including citric acid, succinic acid and malic acid, were significantly elevated after LSG. This is the first report to show dynamic alterations in plasma metabolite concentrations, as assessed using capillary electrophoresis time-of-flight mass spectrometry, in morbidly obese patients after LSG. Our results might show how LSG helps improve obesity, in part through metabolic status changes, and propose novel therapeutic targets to ameliorate obesity.
    Jan. 2021, Journal of diabetes investigation, 12(1) (1), 123 - 129, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Hideya Suehiro, Koji Fukuzawa, Naofumi Yoshida, Kunihiko Kiuchi, Mitsuru Takami, Tomomi Akita, Tokiko Tabata, Makoto Takemoto, Jun Sakai, Toshihiro Nakamura, Atsusuke Yatomi, Hiroyuki Takahara, Yusuke Sonoda, Kazutake Nakasone, Kyoko Yamamoto, Atsushi Suzuki, Tomoya Yamashita, Ken-Ichi Hirata
    Inflammation has been suggested to play a key role in the pathogenesis of atrial fibrillation (AF). Our hypothesis was that this inflammation, mediated by intermediate monocytes and toll-like receptor 4 (TLR4), causes the formation and expansion of low-voltage zones (LVZs). Prior to ablation, the monocyte subsets of 78 AF patients and TLR4 expression of 66 AF patients were analyzed via a flow cytometric analysis. Based on the CD14/CD16 expression, the monocytes were divided into three subsets: classical, intermediate, and non-classical. At the beginning of the ablation session, voltage mapping was performed. LVZs were defined as all bipolar electrogram amplitudes of < 0.5 mV. Correlations between the flow cytometric analysis results and presence of LVZs, as well as the total area of the LVZ, were examined. Patients with LVZs clearly had a higher proportion of intermediate monocytes (10.0 ± 3.6% vs. 7.2 ± 2.7%, p < 0.001) than those without LVZs. TLR4 was much more frequently expressed in the intermediate monocytes than other two monocyte subsets (p < 0.001). Moreover, the TLR4 expression level in intermediate monocytes correlated positively with the total area of the LVZs (r = 0.267, p = 0.030), especially in patients with paroxysmal AF (r = 0.365, p = 0.015). The intermediate monocytes and TLR4 expression positively correlated with LVZs in AF patients.
    Dec. 2020, Heart and vessels, 35(12) (12), 1717 - 1726, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Yoshihiro Saito, Yasushi Tsujimoto, Shunsuke Taito, Masahiro Banno, Yuki Kataoka, Tomoya Yamashita, Ken-Ichi Hirata
    Background: The gut microbiota is involved in the pathophysiology of obesity. It is known that oral antibiotics manipulate the gut microbiota; however, the impact on host metabolism of obese adults without bacterial infection has not been systematically summarized. Methods: We searched for randomized, placebo-controlled trials that investigated the effects of oral antibiotics on the metabolic status in obese adults via Medline, EMBASE, and the Cochrane Library. Primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR), body weight, and rate of diarrhea. Additional outcomes included fasting plasma glucose (FPG), plasma glucagon-like peptide-1 (GLP-1), waist circumference, fecal short-chain fatty acid (SCFA) levels, and all adverse events. We assessed the certainty of evidence based on Grading of Recommendations, Assessment, Development and Evaluations. Results: Among 1,762 articles screened, four studies were eligible for quantitative analysis, two of which were applied to meta-analysis. Oral antibiotics had low influence on HOMA-IR [mean difference (MD) 0.09 (95% CI: -0.96 to 1.13)], body weight [MD 4.1 kg (95% CI: -23.77 to 31.97)], FPG [MD -0.12 mmol/L (95% CI: -0.47 to 0.23)], and GLP-1 [MD 0.20 pmol/L (95% CI: -2.36 to 2.76)] compared to placebo. Antibiotics treatment altered fecal acetate and butyrate levels, but resulted in little difference in propionate levels [MD -13.60 µmol/g (95% CI: -22.43 to -4.77), MD -7.60 µmol/g (-10.97 to -4.23), MD -1.10 µmol/g (95% CI: -4.18 to 1.98), respectively]. Several adverse events, such as sun sensitivity and gastrointestinal discomfort, were reported following antibiotics treatment, but no diarrhea. The certainty of evidence for most outcomes was very low to low, except for fecal SCFAs. Conclusions: Our results indicate that oral antibiotics treatment is insufficient to ameliorate metabolic parameters in obese adults, suggesting that oral antibiotics treatment may not qualify as a therapeutic approach for obesity.
    Sep. 2020, Annals of translational medicine, 8(17) (17), 1059 - 1059, English, International magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Tomoya Yamashita, Shigenobu Kishino, Hikaru Watanabe, Kengo Sasaki, Daisuke Sasaki, Tokiko Tabata, Yuta Sugiyama, Nahoko Kitamura, Yoshihiro Saito, Takuo Emoto, Tomohiro Hayashi, Tomoya Takahashi, Masakazu Shinohara, Ro Osawa, Akihiko Kondo, Takuji Yamada, Jun Ogawa, Ken-Ichi Hirata
    Faecal lipopolysaccharides (LPS) have attracted attention as potent elements to explain a correlation between the gut microbiota and cardiovascular disease (CVD) progression. However, the underlying mechanism of how specific gut bacteria contribute to faecal LPS levels remains unclear. We retrospectively analysed the data of 92 patients and found that the abundance of the genus Bacteroides was significantly and negatively correlated with faecal LPS levels. The controls showed a higher abundance of Bacteroides than that in the patients with CVD. The endotoxin units of the Bacteroides LPS, as determined by the limulus amoebocyte lysate (LAL) tests, were drastically lower than those of the Escherichia coli LPS; similarly, the Bacteroides LPS induced relatively low levels of pro-inflammatory cytokine production and did not induce sepsis in mice. Fermenting patient faecal samples in a single-batch fermentation system with Bacteroides probiotics led to a significant increase in the Bacteroides abundance, suggesting that the human gut microbiota could be manipulated toward decreasing the faecal LPS levels. In the clinical perspective, Bacteroides decrease faecal LPS levels because of their reduced LAL activity; therefore, increasing Bacteroides abundance might serve as a novel therapeutic approach to prevent CVD via reducing faecal LPS levels and suppressing immune responses.
    Corresponding, Springer Science and Business Media LLC, Aug. 2020, Scientific reports, 10(1) (1), 13009 - 13009, English, International magazine
    [Refereed]
    Scientific journal

  • Masato Ogawa, Naofumi Yoshida, Seimi Satomi-Kobayashi, Yasunori Tsuboi, Kodai Komaki, Kumiko Wakida, Yasuko Gotake, Takeshi Inoue, Hiroshi Tanaka, Tomoya Yamashita, Yoshitada Sakai, Kazuhiro P Izawa, Michiko Takahashi, Wataru Ogawa, Ken-Ichi Hirata
    BACKGROUND: Elderly patients undergoing cardiac surgery often show poor nutritional status, muscle wasting, and sarcopenia, which are reported to affect postoperative functional recovery and incidence of complications. Amino acids are essential in maintaining nutritional status, synthesizing muscle protein, and promoting beneficial energy balance of the heart muscle. β-Hydroxy β-methylbutyric acid (HMB) is a leucine metabolite known to increase muscle protein synthesis and inhibit protein catabolism; it has been used to more effectively support patients with muscle wasting due to wearing diseases. However, the efficacy of amino acid administration comprising HMB in patients undergoing open heart surgery remains unclear. This study aims to examine whether preoperative short-term aggressive amino acid administration helps support postoperative recovery of physical function and prevent complications. METHODS: This is a single-center prospective randomized controlled trial (UMIN000030490). Patients aged ≥65 years who will be hospitalized for medical examination before cardiac surgery will be recruited. The participants will be randomly assigned to the experimental or control group. The experimental group will be administered with an amino acid supplement with HMB 1200mg, l-glutamine 7000mg, and l-arginine 7000mg once or twice per day depending on the degree of renal dysfunction, for 14-28 days preoperatively. The control group will not receive any nutritional intervention. The main outcome will be a change in the 6-min walking test distance pre- and postoperatively as a sign of functional recovery. Secondary outcomes such as the incidence of complications; physical, nutritional, and psychological states; mortality; and length of hospital stay will also be evaluated. CONCLUSION: This clinical study will determine the effects of preoperative short-term oral amino acid supplementation with HMB, l-glutamine, and l-arginine on postoperative physical function in elderly patients undergoing cardiac surgery.
    Oct. 2019, Journal of cardiology, 74(4) (4), 360 - 365, English, International magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Kengo Sasaki, Daisuke Sasaki, Tomoya Yamashita, Hajime Fukuda, Tomohiro Hayashi, Tokiko Tabata, Ro Osawa, Ken-Ichi Hirata, Akihiko Kondo
    AIM: Bacteroides vulgatus and B. dorei have a protective effect against atherosclerosis, suggesting that expansion of these species in the gut microbiota could help patients with coronary artery disease (CAD). This study aimed to investigate the effect of resistant starch (RS) on the gut microbiota and its metabolites in fecal sample cultures from patients with CAD and individuals without CAD, using a single-batch fermentation system. METHODS: Fecal samples from 11 patients with CAD and 10 individuals without CAD were fermented for 30 h with or without RS in the Kobe University Human Intestinal Microbiota Model (KUHIMM). Gut microbiota and the abundance of B. vulgatus and B. dorei were analyzed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing and the quantitative polymerase chain reaction. Short-chain fatty acids were analyzed using high-performance liquid chromatography. RESULTS: Gut microbial analysis showed significantly lower levels of B. vulgatus and B. dorei in the original fecal samples from patients with CAD, which was simulated after 30 h of fermentation in the KUHIMM. Although RS significantly increased the absolute numbers of B. vulgatus and B. dorei, and butyrate levels in CAD fecal sample cultures, the numbers varied among each patient. CONCLUSIONS: The effect of RS on gut microbiota and its metabolites in the KUHIMM varied between CAD and non-CAD fecal sample cultures. The KUHIMM may be useful for preclinical evaluations of the effects of RS on the gut microbiota and its metabolites.
    Corresponding, Aug. 2019, Journal of atherosclerosis and thrombosis, 26(8) (8), 705 - 719, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Tomohiro Hayashi, Takuo Emoto, Takuya Matsumoto, Naofumi Yoshida, Tokiko Tabata, Sayo Horibe, Shoji Kawauchi, Yoshiyuki Rikitake, Ken-Ichi Hirata
    Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe-/-) mice or control Apoe-/- mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe-/- mice had reduced accumulation of macrophages and CD4+ T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.
    May 2019, Scientific reports, 9(1) (1), 8065 - 8065, English, International magazine
    [Refereed]
    Scientific journal

  • Tomohiro Hayashi, Tomoya Yamashita, Hikaru Watanabe, Kenjiro Kami, Naofumi Yoshida, Tokiko Tabata, Takuo Emoto, Naoto Sasaki, Taiji Mizoguchi, Yasuhiro Irino, Ryuji Toh, Masakazu Shinohara, Yuko Okada, Wataru Ogawa, Takuji Yamada, Ken-Ichi Hirata
    BACKGROUND: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). CONCLUSIONS: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.
    Corresponding, Dec. 2018, Circulation journal : official journal of the Japanese Circulation Society, 83(1) (1), 182 - 192, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Takuo Emoto, Tomoya Yamashita, Hikaru Watanabe, Tomohiro Hayashi, Tokiko Tabata, Namiko Hoshi, Naoya Hatano, Genki Ozawa, Naoto Sasaki, Taiji Mizoguchi, Hilman Zulkifli Amin, Yushi Hirota, Wataru Ogawa, Takuji Yamada, Ken-Ichi Hirata
    BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.
    Corresponding, Nov. 2018, Circulation, 138(22) (22), 2486 - 2498, English, International magazine
    [Refereed]
    Scientific journal

  • Hiroyuki Yamamoto, Naofumi Yoshida, Toshiro Shinke, Hiromasa Otake, Masaru Kuroda, Kazuhiko Sakaguchi, Yushi Hirota, Takayoshi Toba, Hachidai Takahashi, Daisuke Terashita, Kenzo Uzu, Natsuko Tahara, Yuto Shinkura, Kouji Kuroda, Yoshinori Nagasawa, Yuichiro Nagano, Yoshiro Tsukiyama, Ken-Ichi Yanaka, Takuo Emoto, Naoto Sasaki, Tomoya Yamashita, Wataru Ogawa, Ken-Ichi Hirata
    Data presented in this article are supplementary material to our research article entitled "Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients" [1]. This article contains the data of study population, diagnostic ability of CD14++CD16+ monocytes to identify thin-cap fibroatheromas, and association between laboratory variables and plaque properties.
    Jun. 2018, Data in brief, 18, 172 - 175, English, International magazine
    [Refereed]
    Scientific journal

  • Hiroyuki Yamamoto, Naofumi Yoshida, Toshiro Shinke, Hiromasa Otake, Masaru Kuroda, Kazuhiko Sakaguchi, Yushi Hirota, Takayoshi Toba, Hachidai Takahashi, Daisuke Terashita, Kenzo Uzu, Natsuko Tahara, Yuto Shinkura, Kouji Kuroda, Yoshinori Nagasawa, Yuichiro Nagano, Yoshiro Tsukiyama, Ken-Ichi Yanaka, Takuo Emoto, Naoto Sasaki, Tomoya Yamashita, Wataru Ogawa, Ken-Ichi Hirata
    BACKGROUND AND AIMS: This study examined the impact of CD14++CD16+ monocytes on coronary plaque vulnerability, as assessed by optical coherence tomography (OCT), and investigated their association with daily glucose fluctuation. Although increased CD14++CD16+ monocyte levels have been reported to increase cardiovascular events, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without diabetes mellitus (DM) remains unclear. METHODS: This prospective observational study included 50 consecutive patients with CAD, receiving lipid-lowering therapy and undergoing coronary angiography and OCT. Patients were divided into 3 tertiles according to the CD14++CD16+ monocyte percentages assessed by flow cytometry. Standard OCT parameters were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30-70%). Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). RESULTS: CD14++CD16+ monocytes negatively correlated with fibrous cap thickness (r = -0.508, p < 0.01). The presence of thin-cap fibroatheroma (TCFA) was increased stepwise according to the tertile of CD14++CD16+ monocytes (0 [tertile 1] vs. 5 [tertile 2] vs. 10 [tertile 3], p < 0.01). CD14++CD16+ monocytes were a significant determinant of TCFA (OR 1.279, p = 0.001). In non-DM patients, a significant relationship was found between CD14++CD16+ monocytes and MAGE (r = 0.477, p = 0.018). CONCLUSIONS: CD14++CD16+ monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14++CD16+ monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14++CD16+ monocytes could be a possible therapeutic target for coronary plaque stabilization.
    Feb. 2018, Atherosclerosis, 269, 245 - 251, English, International magazine
    [Refereed]
    Scientific journal

  • Akira Nagasawa, Shumpei Mori, Tomomi Akita, Haruhi Yamada, Tsumugi Oki, Tatsuya Nishii, Tomoya Yamashita, Yutaka Okita, Ken-Ichi Hirata
    Even in modern clinical cardiology, basic auscultation skill is not obsolete and is still important because it can always provide a clue to an underlying pathophysiology. We demonstrate an unusual mechanism of pathological wide splitting of the second heart sound due to external compression of the pulmonary trunk in a patient with a giant coronary arterial aneurysm of the proximal left anterior descending artery. Echocardiography, when combined with a three-dimensional anatomical analysis with cardiac computed tomography, was useful for elucidating the mechanism of the abnormal heart sounds.
    Japanese Society of Internal Medicine, 2018, Internal Medicine, 57(8) (8), 1111 - 1114, English
    [Refereed]
    Scientific journal

  • Tomohiro Hayashi, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Takuo Emoto, Hilman Zulkifli Amin, Keiko Yodoi, Takuya Matsumoto, Kazuyuki Kasahara, Naofumi Yoshida, Tokiko Tabata, Naoki Kitano, Atsushi Fukunaga, Chikako Nishigori, Yoshiyuki Rikitake, Ken-Ichi Hirata
    BACKGROUND: Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. METHODS AND RESULTS: We used an angiotensin II-induced AAA model in apolipoprotein E-deficient mice fed a high-cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB-irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II-infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB-irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para-aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. CONCLUSIONS: Our data suggest that UVB-dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.
    Aug. 2017, Journal of the American Heart Association, 6(9) (9), e007024, English, International magazine
    [Refereed]
    Scientific journal

  • Naofumi Yoshida, Hiroyuki Yamamoto, Toshiro Shinke, Hiromasa Otake, Masaru Kuroda, Daisuke Terashita, Hachidai Takahashi, Kazuhiko Sakaguchi, Yushi Hirota, Takuo Emoto, Hilman Zulkifli Amin, Taiji Mizoguchi, Tomohiro Hayashi, Naoto Sasaki, Tomoya Yamashita, Wataru Ogawa, Ken-Ichi Hirata
    Background: Previously, we have reported that daily glucose fluctuations could affect coronary plaque vulnerability, but the underlying mechanisms remained unclear. This study sought to investigate the impact of -CD14(++) CD16(+) monocytes on plaque vulnerability, as assessed by virtual histology intravascular ultrasound (VH-IVUS), as well as their relationship to fluctuating glucose levels in patients with asymptomatic coronary artery disease (CAD). Methods: Fifty-one patients with asymptomatic CAD, who were undergoing lipid-lowering therapy and underwent VH-IVUS evaluation for angiographically mild to moderate lesions, were enrolled in the study. Standard VH-IVUS parameters, including the percentage volume of the necrotic core (%NC) within the plaque and the presence of a virtual histology thin-cap fibroatheroma (VH-TCFA), were then evaluated. Additionally, monocyte subsets were assessed by flow cytometry, and daily glucose fluctuations were analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results: Among 82 plaques from 22 diabetes mellitus (DM) patients and 29 non-DM patients, 15 VH-TCFAs were identified. -CD14(++) CD16(+) monocyte counts significantly correlated with both %NC and the presence of VH-TCFA (%NC: r = 0.339, p = 0.002; VH-TCFA: p = 0.003). Multivariate logistic regression analysis revealed that -CD14++ CD16+ monocyte counts were independently associated with VH-TCFA (odds ratio = 1.029, p = 0.004). Furthermore, -CD14(++) CD16(+) monocyte counts were significantly correlated with the MAGE score in the non-DM patients (r = 0.544, p = 0.005). Conclusions: CD14(++) CD16(+) monocyte levels are associated with coronary plaque vulnerability and can serve as a biomarker for VH-TCFA in patients with CAD undergoing lipid-lowering therapy. In patients without DM, glucose fluctuations may alter the balance of monocyte subsets.
    BIOMED CENTRAL LTD, Aug. 2017, CARDIOVASCULAR DIABETOLOGY, 16(1) (1), 96, English
    [Refereed]
    Scientific journal

  • Taiji Mizoguchi, Kazuyuki Kasahara, Tomoya Yamashita, Naoto Sasaki, Keiko Yodoi, Takuya Matsumoto, Takuo Emoto, Tomohiro Hayashi, Naoki Kitano, Naofumi Yoshida, Hilman Zulkifli Amin, Ken-Ichi Hirata
    The intestinal microbiota appears to play an important role in the development of atherosclerosis. We investigated the effect of the probiotic lactic acid bacterium Pediococcus acidilactici R037 on atherosclerosis using apolipoprotein E-deficient (ApoE -/-) mice. Six-week-old ApoE -/- mice were orally administered R037 six times a week. Mice treated with R037 for 12 weeks exhibited markedly attenuated atherosclerotic lesions in the aortic root (2.3 ± 0.15 × 105 µm2 vs. 3.3 ± 0.29 × 105 µm2, respectively; P < 0.01; n = 15-17 each group). The expression of Ki-67 in CD4+ T cells, the population of interferon γ-producing CD4+ T cells in the spleen, and pro-inflammatory cytokine production from splenic lymphocytes were significantly decreased in R037-treated mice. Interestingly, splenic dendritic cells (DCs) isolated from R037-treated mice suppressed CD4+ T-cell proliferation and pro-inflammatory cytokine production ex vivo, suggesting that R037 treatment induced tolerogenic DCs. Programmed cell death ligand 1 expression in DCs was significantly enhanced in R037-treated mice, which might explain the immunosuppressive effect of DCs at least in part. These results indicate that R037 attenuates atherosclerosis by inducing tolerogenic DCs, which suppress Th1-driven inflammation and the proliferative activity of CD4+ T cells. Our findings may provide a novel therapeutic approach for the prevention of atherosclerosis based on dietary supplementation with probiotics.
    Corresponding, Jun. 2017, Heart and vessels, 32(6) (6), 768 - 776, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Feibi Zeng, Tomofumi Takaya, Naofumi Yoshida, Tatsuro Ito, Makiko Suto, Yu Hatani, Hiroyuki Sano, Jun Ito, Hidenori Fukuoka, Tomoya Yamashita, Ken-Ichi Hirata
    A 36-year-old man with a history of Graves' disease was admitted complaining of dyspnea. He was diagnosed with acute heart failure and severe liver dysfunction accompanied by thyroid storm. Left ventricular ejection fraction was 19%, and liver enzyme levels were markedly elevated followed with coagulation disorders. In addition to the conventional therapy, we performed plasma exchange emergently. Thyroid hormone levels promptly normalized, then his clinical condition improved. Finally, his cardiac and liver function almost normalized from a fatal condition without serious complications. Hyperthyroidism can cause myocardial and liver injury, hence thyroid hormone removal in acute phase is important. Prompt plasma exchange is effective in the acute phase for heart and liver failure accompanied by thyroid storm. .
    Mar. 2017, Journal of cardiology cases, 15(3) (3), 100 - 103, English, Domestic magazine
    [Refereed]

  • Kazuyuki Kasahara, Takeshi Tanoue, Tomoya Yamashita, Keiko Yodoi, Takuya Matsumoto, Takuo Emoto, Taiji Mizoguchi, Tomohiro Hayashi, Naoki Kitano, Naoto Sasaki, Koji Atarashi, Kenya Honda, Ken-ichi Hirata
    The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free (GF) or conventionally raised (Conv) Apolipoprotein E deficient (ApoE(-/-)) mice were fed chow diet and sacrificed at twenty weeks of age. We found lack of gut microbiota in ApoE(-/-) mice caused a significant increase in the plasma and hepatic cholesterol levels compared to ConvR ApoE(-/-) mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the entero-hepatic fibroblast growth factor 15 (FGF15) - fibroblast growth factor receptor 4 (FGFR4) axis, and reduction of cholesterol 7a-hydroxylase (CYP7A1) and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared to Conv ApoE(-/-) mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice.
    ELSEVIER, Mar. 2017, JOURNAL OF LIPID RESEARCH, 58(3) (3), 519 - 528, English
    [Refereed]
    Scientific journal

  • Naoto Sasaki, Tomoya Yamashita, Kazuyuki Kasahara, Atsushi Fukunaga, Tomoyuki Yamaguchi, Takuo Emoto, Keiko Yodoi, Takuya Matsumoto, Kenji Nakajima, Tomoyuki Kita, Masafumi Takeda, Taiji Mizoguchi, Tomohiro Hayashi, Yoshihiro Sasaki, Mayumi Hatakeyama, Kumiko Taguchi, Ken Washio, Shimon Sakaguchi, Bernard Malissen, Chikako Nishigori, Ken-ichi Hirata
    Objective-UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results-Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4(+) forkhead box P3(+) regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4(+) forkhead box P3(+) regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions-Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.
    LIPPINCOTT WILLIAMS & WILKINS, Jan. 2017, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 37(1) (1), 66 - +, English
    [Refereed]
    Scientific journal

  • Atsushi Suzuki, Koji Fukuzawa, Tomoya Yamashita, Akihiro Yoshida, Naoto Sasaki, Takuo Emoto, Asumi Takei, Ryudo Fujiwara, Tomoyuki Nakanishi, Soichiro Yamashita, Akinori Matsumoto, Hiroki Konishi, Hirotoshi Ichibori, Ken-ichi Hirata
    Aims A recent large clinical study demonstrated the association between intermediate CD14++CD16+monocytes and cardiovascular events. However, whether that monocyte subset contributes to the pathogenesis of atrial fibrillation (AF) has not been clarified. We compared the circulating monocyte subsets in AF patients and healthy people, and investigated the possible role of intermediate CD14++CD16+monocytes in the pathophysiology of AF. Methods and results This case-control study included 44 consecutive AF patients without systemic diseases referred for catheter ablation at our hospital, and 40 healthy controls. Patients with systemic diseases, including structural heart disease, hepatic or renal dysfunction, collagen disease, malignancy, and inflammation were excluded. Monocyte subset analyses were performed (three distinct human monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+, and non-classical CD14+CD16++monocytes). We compared the monocyte subsets and evaluated the correlation with other clinical findings. A total of 60 participants (30 AF patients and 30 controls as an age-matched group) were included after excluding 14 AF patients due to inflammation. Atrial fibrillation patients had a higher proportion of circulating intermediate CD14++CD16+monocytes than the controls (17.0 +/- 9.6 vs. 7.5 +/- 4.1%, P < 0.001). A multivariable logistic regression analysis demonstrated that only the proportion of intermediate CD14++CD16+monocytes (odds ratio: 1.316; 95% confidence interval: 1.095-1.582, P = 0.003) was independently associated with the presence of AF. Intermediate CD14++CD16+monocytes were negatively correlated with the left atrial appendage flow during sinus rhythm (r = -0.679, P = 0.003) and positively with the brain natriuretic peptide (r = 0.439, P = 0.015). Conclusion Intermediate CD14++CD16+monocytes might be closely related to the pathogenesis of AF and reflect functional remodelling of the left atrium.
    OXFORD UNIV PRESS, Jan. 2017, EUROPACE, 19(1) (1), 40 - 47, English
    [Refereed]
    Scientific journal

  • Takuo Emoto, Tomoya Yamashita, Toshio Kobayashi, Naoto Sasaki, Yushi Hirota, Tomohiro Hayashi, Anna So, Kazuyuki Kasahara, Keiko Yodoi, Takuya Matsumoto, Taiji Mizoguchi, Wataru Ogawa, Ken-ichi Hirata
    The association between atherosclerosis and gut microbiota has been attracting increased attention. We previously demonstrated a possible link between gut microbiota and coronary artery disease. Our aim of this study was to clarify the gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism (T-RFLP). This study included 39 coronary artery disease (CAD) patients and 30 age- and sex- matched no-CAD controls (Ctrls) with coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by T-RFLP and data mining analysis using the classification and regression algorithm. Five additional CAD patients were newly recruited to confirm the reliability of this analysis. Data mining analysis could divide the composition of gut microbiota into 2 characteristic nodes. The CAD group was classified into 4 CAD pattern nodes (35/39 = 90 %), while the Ctrl group was classified into 3 Ctrl pattern nodes (28/30 = 93 %). Five additional CAD samples were applied to the same dividing model, which could validate the accuracy to predict the risk of CAD by data mining analysis. We could demonstrate that operational taxonomic unit 853 (OTU853), OTU657, and OTU990 were determined important both by the data mining method and by the usual statistical comparison. We classified the gut microbiota profiles in coronary artery disease patients using data mining analysis of T-RFLP data and demonstrated the possibility that gut microbiota is a diagnostic marker of suffering from CAD.
    Corresponding, SPRINGER, Jan. 2017, HEART AND VESSELS, 32(1) (1), 39 - 46, English
    [Refereed]
    Scientific journal

  • Monocyte-to-HDL-cholesterol ratio and left atrial remodelling in atrial fibrillation: author's reply
    SuzukiA, Fukuzawa Koji, Yamashita Tomoya, SasakiN, Hirata Ken-ichi
    Oct. 2016, Europace, 19(19) (19), 40 - 47, English
    [Refereed]
    Scientific journal

  • Takuya Matsumoto, Naoto Sasaki, Tomoya Yamashita, Takuo Emoto, Kazuyuki Kasahara, Taiji Mizoguchi, Tomohiro Hayashi, Keiko Yodoi, Naoki Kitano, Takashi Saito, Tomoyuki Yamaguchi, Ken-ichi Hirata
    Objective-Although T-cell-mediated chronic inflammation contributes to atherosclerosis development, the role of a negative regulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in atherosclerosis is poorly understood. We investigated the effects of CTLA-4 overexpression on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice. Approach and Results-We generated CTLA-4 transgenic (CTLA-4-Tg)/Apoe(-/-) mice that display constitutive cell surface and intracellular expression of CTLA-4 in T cells and assessed atherosclerosis at age 16 weeks. CTLA-4 overexpression significantly reduced atherosclerotic lesion formation and intraplaque accumulation of macrophage and CD4(+) T cells in the aortic root compared with controls. CTLA-4-Tg/Apoe(-/-) mice showed decreased numbers of effector CD4(+) T cells and decreased expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, and a costimulatory molecule CD28, on CD11c(+) dendritic cells compared with controls. Consistent with in vivo findings, in vitro experiments revealed that CD4(+) T cells from CTLA-4-Tg/Apoe(-/-) mice showed decreased proliferative capacity and proinflammatory cytokine production, downregulated CD80 expression on CD11c(+) dendritic cells, and suppressed the proliferation of other T cells by limiting the costimulatory pathway. Moreover, CD11c(+) dendritic cells from CTLA-4-Tg/Apoe(-/-) mice showed reduced proliferative activity of T cells in vitro, suggesting the suppression of dendritic cell maturation in vivo. Conclusions-CTLA-4 regulates atherosclerosis by suppressing proatherogenic immune responses and could be an attractive therapeutic target for atherosclerosis.
    LIPPINCOTT WILLIAMS & WILKINS, Jun. 2016, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 36(6) (6), 1141 - U224, English
    [Refereed]
    Scientific journal

  • Hirata Ken-ichi, Yamashita Tomoya
    The Japanese Society of Internal Medicine, 2016, Nihon Naika Gakkai Zasshi, 105(9) (9), 1706 - 1711, Japanese

  • Takuo Emoto, Tomoya Yamashita, Naoto Sasaki, Yushi Hirota, Tomohiro Hayashi, Anna So, Kazuyuki Kasahara, Keiko Yodoi, Takuya Matsumoto, Taiji Mizoguchi, Wataru Ogawa, Ken-ichi Hirata
    Aim: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD). Methods: This study included 39 CAD patients, 30 age-and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism. Results: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6%+/- 12.0%, 6.2%+/- 7.7% vs. 4.1%+/- 5.9%; p< 0.001) and the phylum Bacteroidetes (Bacteroides+ Prevotella) was decreased (CAD, Ctrl vs. HV; 35.5%+/- 11.6%, 43.9%+/- 11.2% vs. 47.4%+/- 11.5%; p< 0.001). The CAD group was over-represented in enterotype "others" (III), compared with the Ctrl or HV group (p< 0.001, chi-squared test), although we could not deny the possibility that some drugs affect the gut flora types. Conclusions: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota.
    Corresponding, JAPAN ATHEROSCLEROSIS SOC, 2016, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 23(8) (8), 908 - +, English
    [Refereed]
    Scientific journal

  • Gut microbiota and cardiovascular disease
    Takuo Emoto, Tomoya Yamashita, Ken-Ichi Hirata
    Japanese Journal of Clinical Chemistry, Oct. 2015, Japanese Journal of Clinical Chemistry, 44(4) (4), 282 - 289, Japanese
    Scientific journal

  • アンジオテンシンII誘発性大動脈瘤形成に対するn-3系多価不飽和脂肪酸EPAとDHAの差異の検討
    淀井景子, Yamashita Tomoya, 河野浩之, 佐々木直人, 北智之, 笠原和之, 佐々木義浩, 松本卓也, 江本拓央, 溝口泰司, 林友鴻, Hirata Ken-ichi
    Oct. 2015, 薬理と治療, 43(10号) (10号), 1409 - 1416, Japanese
    [Refereed]
    Research society

  • H. Kawano, H. Tanaka, T. Yamashita, K. I. Hirata, S. Ishii, T. Suzuki, K. Wakahashi, Y. Kawano, A. Sada, K. Minagawa, F. Kawakami, T. Itoh, A. Baba, T. Matsui, Y. Katayama
    Jun. 2015, Bone Marrow Transplantation, 50(6) (6), 870 - 872, English
    [Refereed]
    Scientific journal

  • Keiko Yodoi, Tomoya Yamashita, Naoto Sasaki, Kazuyuki Kasahara, Takuo Emoto, Takuya Matsumoto, Tomoyuki Kita, Yoshihiro Sasaki, Taiji Mizoguchi, Tim Sparwasser, Ken-ichi Hirata
    Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3(+) Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3(+) Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E-deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II-infused mice received interleukin-2/anti-interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II-infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3(+) Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3(+) Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3(+) Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3(+) Tregs against AAA. Our findings suggest that Foxp3(+) Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.
    LIPPINCOTT WILLIAMS & WILKINS, Apr. 2015, HYPERTENSION, 65(4) (4), 889 - +, English
    [Refereed]
    Scientific journal

  • Investigation of the differential effects of n-3 polyunsaturated fatty acids, EPA and DHA, on angiotensin II-induced aortic aneurysm formation in mice
    Keiko Yodoi, Tomoya Yamashita, Naoto Sasaki, Tomoyuki Kita, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuya Matsumoto, Takuo Emoto, Taiji Mizoguchi, Tomohiro Hayashi, Kerrichi Hirata, Hiroyuki Kawano
    Background Accumulating evidence suggested that n-3 polyunsaturated fatty acids (PUFAs) were associated with reduction of cardiovascular events. However, it remains unclear whether n-3 PUFAs have protective role in abdominal aortic aneurysm (AAA) formation. Methods 6-week-old apolipoprotein E-deficient mice were fed a high n-3 PUFA diet (EPA, EPA+DHA, and DHA) or normal diet with high cholesterol. Angiotensin II (n = 62) or normal saline (n=6) were continuously infused from 12 weeks old by implanting osmotic mini-pumps and AAA formation was evaluated at 16 weeks. Results Seventy-five percent of angiotensin II-infused mice with EPA treatment developed AAA formation, 100% with EPA+DHA treatment and 88.9% with DHA treatment. The severity of AAA was slightly reduced in EPA treatment group. The mortality rates of each treatment group (EPA, EPA + DHA, and DHA) were 12.5%, 25.0% and 28.6%, respectively. Flow cytometric analyses revealed that EPA treatment increased Foxp3 positive regulatory T cells and effector T cells. The proportions of mature dendritic cells were not significantly different among those three treatment groups. Conclusion This study suggests that dietary supplementation with EPA might potentially have a protective role in AAA formation and reduce the mortality of AAA. More precise mechanisms are elucidated and promotion of n-3 PUFAs intake may represent a novel therapeutic approach to AAA.
    Life Science Publishing Co. Ltd, 2015, Japanese Pharmacology and Therapeutics, 43(10) (10), 1409 - 1416, Japanese
    Scientific journal

  • Takuo Emoto, Naoto Sasaki, Tomoya Yamashita, Kazuyuki Kasahara, Keiko Yodoi, Yoshihiro Sasaki, Takuya Matsumoto, Taiji Mizoguchi, Ken-ichi Hirata
    Background: The protective function of regulatory T cells (T-reg) has been identified in experimental atherosclerosis, but the contribution of T-reg to the pathogenesis of human coronary artery disease (CAD) remains poorly understood. We investigated T-reg and regulatory T-cell/effector T-cell (T-reg/T-eff) ratio in peripheral blood samples from CAD patients using a new strategy for precise identification of T-reg. Methods and Results: Peripheral blood samples were collected from 73 stable CAD patients (55 middle-aged CAD patients and 18 old CAD patients) and 64 controls (47 middle-aged controls and 17 young controls). CD3(+)CD4(+)FoxP3(+) T cells were divided into 3 fractions: CD45RA(+)FoxP3(low) resting T-reg (Fr1), CD45RA(-)FoxP3(high) activated T-reg (Fr2), and CD45RA(-)FoxP3(low) non-T-reg (Fr3). CAD patients had lower percentages of Fr1 and Fr2 and higher percentages of Fr3 and CD45RA(-)Foxp3(-) T-eff (Fr4+5) within the CD3(+)CD4(+) T-cell population compared to age-matched controls. T-reg/T-eff ratio (Fr1+2/Fr3+4+5) in CAD patients was also markedly lower than in controls (middle-aged control, 0.17+/-0.09 vs. middle-aged CAD, 0.10+/-0.05; P<0.001). The percentage of CD4(+)CD28(null) T cells within the CD4(+) T-cell population was negatively correlated with T-reg/T-eff ratio, excluding CD4(+)CD28(null) T cells <0.3% (r=-0.27, P<0.05). High-sensitivity C-reactive protein was also negatively correlated with T-reg/T-eff ratio (r=-0.22, P<0.05). Conclusions: CAD patients had reduced T-reg and T-reg/T-eff ratio compared to healthy controls. The present findings may be helpful when developing immunotherapy for the prevention of CAD.
    JAPANESE CIRCULATION SOC, Dec. 2014, CIRCULATION JOURNAL, 78(12) (12), 2935 - 2941, English
    [Refereed]
    Scientific journal

  • Shumpei Mori, Tomoya Yamashita, Tomofumi Takaya, Mitsuo Kinugasa, Sachiko Takamine, Mayumi Shigeru, Tatsuro Ito, Sei Fujiwara, Tatsuya Nishii, Atsushi K. Kono, Ken-ichi Hirata
    Age-related morphological changes of the aorta, including dilatation and elongation, have been reported. However, rotation has not been fully investigated. We focused on the rotation of the ascending aorta and investigated its relationship with tortuosity. One hundred and two consecutive patients who underwent computed tomography coronary angiography were studied. The angle at which the en face view of the volume-rendered image of the right coronary aortic sinus (RCS) was obtained without foreshortening was defined as the rotation index. It was defined as zero if the RCS was squarely visible in the frontal view, positive if it rotated clockwise toward the left anterior oblique (LAO) direction, and negative if it rotated counter-clockwise toward the right anterior oblique (RAO) direction. The tortuosity was evaluated by measuring the biplane tilt angles formed between the ascending aorta and the horizontal line. The mean rotation index, posterior tilt angle viewed fromthe RAO direction (alpha(RAO)), and anterior tilt angle viewed from the LAO direction (alpha(LAO)) were 4.8 +/- 16.3, 60.7 +/- 7.0 degrees, and 63.6 +/- 9.0 degrees, respectively. Although no correlation was observed between the rotation index and the alpha(LAO) (beta=-0.0761, P=0.1651), there was a significant negative correlation between the rotation index and alpha(RAO) (beta=-0.1810, P<0.0001). In multivariate regression analysis, the rotation index was an independent predictor of the alpha(RAO) (beta=-0.1274, P50.0008). Clockwise rotation of the proximal ascending aorta exacerbates the tortuosity by tilting the aorta toward the posterior direction. (C) 2014 Wiley Periodicals, Inc.
    WILEY-BLACKWELL, Nov. 2014, CLINICAL ANATOMY, 27(8) (8), 1200 - 1211, English
    [Refereed]
    Scientific journal

  • [Thrombopoietin receptor agonists administration for acute exacerbation of chronic idiopathic thrombocytopenic purpura and subsequent anticoagulant therapy for accompanying deep venous thrombosis of the lower limbs]
    Kawano H, Suzuki T, Ishii S, Wakahashi K, Kawano Y, Sada A, Minagawa K, Takaya T, Yamashita T, Hirata Ken-ichi, Koriyama K, Nagamatsu Y, Matsui T, Katayama Y
    We report two patients (70- and 49-year-old Japanese men) with acute exacerbation of chronic idiopathic thrombocytopenic purpura (ITP) and deep venous thrombosis of the lower extremities. Both were successfully managed with thrombopoietin receptor agonist (TPO-RA) administration. Both had ITP refractory to steroid treatment. Their immature platelet fraction (absolute-IPF) counts were increased and paralleled the platelet recoveries after TPO-RA (eltrombopag and romiplostim, respectively) without progression of thrombosis. Although ITP has recently been evaluated as a thrombophilic disorder, reports on acute exacerbation of ITP with newly diagnosed thrombosis are limited, and the pathophysiology and association between ITP and thrombosis remain to be elucidated. Moreover, the influences of TPO-RA on thrombosis are still controversial. To our knowledge, this is the first case report describing patients with exacerbation of ITP who developed thrombosis and were treated with TPO-RA. The outcomes of our cases underscore the importance of monitoring thrombosis and not delaying the initiation of anticoagulation treatment during the use of TPO-RA.
    Jun. 2014, Rinsho Ketsueki, 55(6) (6), 697 - 702, English, Domestic magazine
    [Refereed]
    Scientific journal

  • TPO受容体作動薬を使用し抗凝固療法への移行が可能であった下肢深部静脈血栓症合併慢性ITP急性増悪
    川野宏樹, 鈴木知秀, 石井慎一, 若橋香奈子, 川野裕子, 定明子, 皆川健太郎, Takaya Tomofumi, Yamashita Tomoya, Hirata Ken-ichi, 郡山健治, 永松裕一, MATSUI TOSHIMITSU, KATAYAMA YOSHIO
    Jun. 2014, 臨床血液, 55(6号) (6号), 697 - 702, Japanese
    [Refereed]
    Scientific journal

  • Tomoyuki Kita, Tomoya Yamashita, Naoto Sasaki, Kazuyuki Kasahara, Yoshihiro Sasaki, Keiko Yodoi, Masafumi Takeda, Kenji Nakajima, Ken-ichi Hirata
    Aims Although recent animal studies have investigated the cellular and molecular mechanisms underlying the process of atherosclerosis regression, it remains unknown whether adaptive immune responses including T cells are involved in this process. We investigated the role of T cells in atherosclerosis regression. Methods and results LDL receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to form atherosclerotic lesions and were then changed to a standard diet, and atherosclerosis was assessed 4 weekslater. Just before changing the diet, the mice received an iv injection of anti-CD3 antibody (CD3-Ab) or control immunoglobulin G for 5 consecutive days. CD3-Ab treatment regressed atherosclerosis and decreased the accumulation of macrophages and CD4(+) T cells in the plaques. CD3-Ab treatment also dramatically reduced CD4(+) T cells and increased the proportion of regulatory T cells (Tregs). Depletion of Tregs by anti-CD25 antibody injection abolished the regression of atherosclerosis seen in CD3-Ab-treated mice, indicating the essential role for Tregs in this process. Conclusion CD3-Ab treatment induced rapid regression of established atherosclerosis via reducing CD4(+) T cells and increasing the proportion of Tregs. These findings suggest that therapeutic intervention for T-cell-mediated immune responses may represent a novel strategy to induce atherosclerosis regression in combination with lipid-lowering therapy.
    OXFORD UNIV PRESS, Apr. 2014, CARDIOVASCULAR RESEARCH, 102(1) (1), 107 - 117, English
    [Refereed]
    Scientific journal

  • Wulan Bao, Keisuke Morimoto, Tomomi Hasegawa, Naoto Sasaki, Tomoya Yamashita, Kenichi Hirata, Yutaka Okita, Kenji Okada
    Objective: Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel antidiabetic drug, has a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. However, the effect of DPP-4 inhibitor on aneurysm formation has not been investigated. We aimed to test the hypothesis that the DPP-4 inhibitor, alogliptin, attenuates vascular oxidative stress and thus inhibits abdominal aortic aneurysm (AAA) formation. Methods: AAAs were created with intraluminal elastase and extraluminal calcium chloride in 36 male rats. Rats were divided into three groups: a low dose of alogliptin group (group LD; 1 mg/kg/d), a high-dose group (group HD; 3 mg/kg/d), and a control group (group C, water). Alogliptin was administered by gastric gavage once daily beginning 3 days before surgery. On day 7 after aneurysm preparation, reactive oxygen species (ROS) expression was semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Blood glucose concentrations were measured. Hematoxylin and eosin and elastica Van Gieson stainings were performed on day 28, and the AAA dilatation ratio was calculated. Results: On day 7 (six in each group), dihydroethidium staining of the aneurysm wall showed a reduced level of ROS expression (4.6 +/- 0.6 in group C, 2.7 +/- 0.3 in group LD, and 1.7 +/- 0.5 in group HD; P<.0001) and showed fewer 8-OHdG-positive cells in alogliptin-treated samples (138.1 +/- 7.4 cells in group C, 102.5 +/- 4.5 cells in group LD, and 66.1 +/- 4.5 cells in group HD; P<.0001) The treatment significantly reduced messenger RNA expression of matrix metalloproteinases (MMPs) in aneurysm walls (relative expression: MMP-2: 2.1 +/- 0.4 in group C, 1.3 +/- 0.3 in group LD, and 0.9 +/- 0.2 in group HD; P<.001; MMP-9: 2.0 +/- 0.5 in group C, 0.3 +/- 0.3 in group LD, and 0.3 +/- 0.2 in group HD; P<.001). On day 28 (six in each group), the aortic wall in groups LD and HD was less dilated (dilatation ratio: 199.2% +/- 11.8% in group C, 159.6% +/- 2.8% in group LD, and 147.1% +/- 1.9% in group HD; P<.02 group C vs HD) and had higher elastin content than in group C. The difference in blood glucose levels among the three groups was not significant. Conclusions: The DPP-4 inhibitor, alogliptin, attenuates aneurysm formation and expansion dose-dependently in a rat AAA model via an antioxidative action.
    MOSBY-ELSEVIER, Apr. 2014, JOURNAL OF VASCULAR SURGERY, 59(4) (4), 1098 - 1108, English
    [Refereed]
    Scientific journal

  • Kazuyuki Kasahara, Naoto Sasaki, Tomoya Yamashita, Tomoyuki Kita, Keiko Yodoi, Yoshihiro Sasaki, Masafumi Takeda, Ken-ichi Hirata
    Background-Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti-CD3 antibody (CD3-Ab) and IL-2/anti-IL-2 monoclonal antibody complex (IL-2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. Methods and Results-We treated apolipoprotein E-deficient mice fed a high-cholesterol diet with vehicle, CD3-Ab, IL-2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD3-Ab or IL-2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C(high) inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. Conclusions-Our results indicate that in addition to suppressing Teff responses, enhancing Treg-mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.
    WILEY-BLACKWELL, Apr. 2014, JOURNAL OF THE AMERICAN HEART ASSOCIATION, 3(2) (2), e000719, English
    [Refereed]
    Scientific journal

  • Yoichiro Sugizaki, Hidekazu Tanaka, Junichi Imanishi, Akihide Konishi, Tomoya Yamashita, Toshiro Shinke, Tatsuro Ishida, Hiroya Kawai, Ken-ichi Hirata
    A 65-year-old man was referred to our hospital due to an acute onset of dyspnea and persistent fever. Echocardiography revealed an ejection fraction (EF) of 25% with diffuse severe left ventricular (LV) dysfunction. 18F-fluorodeoxy glucose-positron emission tomography imaging showed significantly increased uptake by the LV and right ventricular walls, indicating active inflammation. The histologic findings of the endomyocardial biopsy specimens indicated the presence of epithelioid cell granuloma. The final diagnosis was thus cardiac sarcoidosis with acute inflammation. Five-months after the initiation of steroid therapy, echocardiography showed an EF of 50%. This is a rare case in which acute inflammation led to acute heart failure mimicking acute myocarditis.
    JAPAN SOC INTERNAL MEDICINE, 2013, INTERNAL MEDICINE, 52(1) (1), 71 - 74, English
    [Refereed]
    Scientific journal

  • Claudia Eberle, Esther Merki, Tomoya Yamashita, Susie Johnson, Aaron M. Armando, Oswald Quehenberger, Claudio Napoli, Wulf Palinski
    Maternal immunization with oxidized lipoproteins prior to pregnancy protects against atherogenic in utero programming by gestational hypercholesterolemia and enhances beneficial lymphocyte-dependent immune responses in offspring. To determine whether in utero programming and immunomodulation also affect insulin resistance (IR) and type 2 diabetes, we investigated the effects of immunization on glucose and insulin responses in LDL receptor-deficient mice fed regular or 60% sucrose diets, as well as in offspring fed 0.5% cholesterol or 60% sucrose diets. IR was assessed by fasting glucose and insulin levels, oral glucose tolerance tests, glucose clamps, pancreatic immunohistochemistry and plasma free fatty acid concentrations. Immunizations improved glucose responses in both genders and protected both immunized mice and their offspring against IR and type 2 diabetes. Protection occurred even under euglycemic conditions, but was greatest in obese males exposed to very obesogenic/diabetogenic conditions. Hyperinsulinemic euglycemic clamps confirmed that maternal immunization protected mainly by reducing IR, but pancreatic immunocytochemistry also indicated some protection against beta cell damage. Maternal immunization was associated with marked regulation in offspring of 4 genes relevant to diabetes and 19 genes of importance for oxidative stress, as well as increased hepatic activities of key antioxidant enzymes. These findings establish that targeted immunomodulation may be used to protect immunized subjects and their offspring against IR and type 2 diabetes, and thus to reduce cardiovascular risk. They also support the notion that in utero programming influences offspring disease not by a single mechanism, but by multiple systemic effects.
    PUBLIC LIBRARY SCIENCE, Sep. 2012, PLOS ONE, 7(9) (9), e45361, English
    [Refereed]
    Scientific journal

  • Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Hideto Tawa, Kenji Nakajima, Atsushi Momose, Ken-ichi Hirata
    We have applied an imaging system of phase-contrast X-ray CT to the detection of atherosclerotic plaque components by means of the differences of tissue mass densities. In this study, we investigated the effect of the anti-platelet therapies, widely used for secondly prevention of cardiovascular events, on plaque stability and examined whether this novel technique could detect the changes of plaque components under the therapy. Apolipoprotein E-deficient mice were fed on high-cholesterol diet alone and either with 0.1% cilostazol or clopidogrel for 10 weeks. We assessed atherosclerotic lesion volumes and components at brachiocephalic artery by the phase-contrast X-ray CT imaging and histochemistry. The phase-contrast X-ray CT imaging could reveal that cilostazol and clopidogrel significantly decreased atherosclerotic lesion volumes at brachiocephalic artery (31.2% reduction in cilostazol group and 37.4% reduction in clopidogrel group), compared with control group. In addition, the mass densities calculated by this method revealed the anti-platelet treatment increased stable plaque areas including high collagen content, but decreased unstable plaque areas including lipid and macrophage content. These findings were confirmed by histological analyses. Real-time PCR analyses indicated that anti-platelets inhibited gene expressions of cytokines and adhesion molecules, such as IFN gamma and ICAM-1. Anti-platelet therapies had a beneficial effect on plaque stability maybe due to anti-inflammatory actions. Phase-contrast X-ray CT imaging could quantify the plaque volume and qualify the plaque components affected by anti-platelet therapies. This novel phase-contrast X-ray CT imaging system could be a plausible method to detect the unstable plaque non-invasively in the future.
    Corresponding, SPRINGER, Jun. 2012, INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, 28(5) (5), 1181 - 1191, English
    [Refereed]
    Scientific journal

  • Expression of Endothelial Lipase Correlates with the Size of Neointima in a Murine Model of Vascular Remodeling
    Li Sun, Tatsuro Ishida, Takeaki Okada, Tomoyuki Yasuda, Tetsuya Hara, Ryuji Toh, Masakazu Shinohara, Tomoya Yamashita, Yoshiyuki Rikitake, Ken-ichi Hirata
    Aim: Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice. Methods: Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells. Results: Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin.-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth. Conclusion: EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration. J Atheroscler Thromb, 2012; 19:1110-1127.
    JAPAN ATHEROSCLEROSIS SOC, 2012, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(12) (12), 1110 - 1127, English
    [Refereed]
    Scientific journal

  • Kenji Nakajima, Tomoya Yamashita, Tomoyuki Kita, Masafumi Takeda, Naoto Sasaki, Kazuyuki Kasahara, Masakazu Shinohara, Yoshiyuki Rikitake, Tatsuro Ishida, Mitsuhiro Yokoyama, Ken-ichi Hirata
    Objective-Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. Methods and Results-LDL-receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (-22.7%, P < 0.05) and decreased the content of macrophages, CD4(+) T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c(+) CD80(-) CD86(-)), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4(+) T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. Conclusion-In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence. (Arterioscler Thromb Vasc Biol. 2011;31:1963-1972.)
    Corresponding, LIPPINCOTT WILLIAMS & WILKINS, Sep. 2011, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 31(9) (9), 1963 - U124, English
    [Refereed]
    Scientific journal

  • Oswald Quehenberger, Tomoya Yamashita, Aaron M. Armando, Edward A. Dennis, Wulf Palinski
    OBJECTIVE: Maternal immunization with oxidized low-density lipoprotein prior to pregnancy prevents pathogenic in utero programming by gestational hypercholesterolemia, but it is unknown whether gestational hypercholesterolemia and maternal immunization affect similar pathways. STUDY DESIGN: A lipidomic approach was used for unbiased plasma eicosanoid profiling in adult offspring of immunized and nonimmunized normocholesterolemic or hypercholesterolemic rabbit mothers. RESULTS: Gestational hypercholesterolemia was associated with increased levels of some eicosanoids formed by the cyclooxygenase and 12-lipoxygenase pathways only (including thromboxane B(2), prostaglandin [PG] F(2 alpha), PGE(2), and PGD(2)). Immunization of hypercholesterolemic or normocholesterolemic mothers reduced 9 of 14 eicosanoids of the cyclooxygenase pathway, 21 of 23 eicosanoids of the 5- and 12-lipoxygenase pathways (eg, 5-hydroxyeicosatetraenoic acid, hepoxilin B(3), 12-hydroxyeicosatetraenoic acid), 8 of 19 eicosanoids of the cytochrome P-450 pathway, and all metabolites of the nonenzymatic pathway. CONCLUSION: Maternal immunization not only counteracts in utero programming by gestational hypercholesterolemia but reduces a broad range of eicosanoid modulators of immunity and inflammation in offspring.
    MOSBY-ELSEVIER, Aug. 2011, AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 205(2) (2), English
    [Refereed]
    Scientific journal

  • Masafumi Takeda, Tomoya Yamashita, Naoto Sasaki, Kenji Nakajima, Tomoyuki Kita, Masakazu Shinohara, Tatsuro Ishida, Ken-ichi Hirata
    Objective-To determine whether the administration of an active form of vitamin D-3 (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. Methods and Results-Recent clinical studies have shown that lack of vitamin D-3 is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4(+) T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3(+) regulatory T cells and a decrease in CD80(+) CD86(+) dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol-treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c(+) DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell-dependent manner but also partly because of a decrease in DC maturation. Conclusion-Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis. (Arterioscler Thromb Vasc Biol. 2010;30:2495-2503.)
    Corresponding, LIPPINCOTT WILLIAMS & WILKINS, Dec. 2010, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 30(12) (12), 2495 - U305, English
    [Refereed]
    Scientific journal

  • Naoto Sasaki, Tomoya Yamashita, Masafumi Takeda, Masakazu Shinohara, Kenji Nakajima, Hideto Tawa, Takashi Usui, Ken-ichi Hirata
    Background-Accumulating evidence suggests that several subsets of regulatory T cells that actively mediate immunologic tolerance play crucial roles in atherogenesis. Recently, orally administered anti-CD3 monoclonal antibody has been shown as an inducer of novel regulatory T cells expressing latency-associated peptide (LAP) on their surface, which potently prevents systemic autoimmunity. In the present study, we hypothesized that oral anti-CD3 antibody treatment may inhibit atherosclerosis in mice. Methods and Results-Six-week-old apolipoprotein E-deficient mice on a standard diet were orally given anti-CD3 antibody or control immunoglobulin G on 5 consecutive days, and atherosclerosis was assessed at age 16 weeks. Oral administration of anti-CD3 antibody significantly reduced atherosclerotic lesion formation and accumulations of macrophages and CD4(+) T cells in the plaques compared with controls. We observed a significant increase in LAP(+) cells and CD25(+)Foxp3(+) cells in the CD4(+) T-cell population in anti-CD3-treated mice, in association with increased production of the antiinflammatory cytokine transforming growth factor-beta and suppressed T-helper type 1 and type 2 immune responses. Neutralization of transforming growth factor-beta in vivo abrogated the preventive effect of oral anti-CD3 antibody. Conclusions-Our findings indicate the atheroprotective role of oral anti-CD3 antibody treatment in mice via induction of a regulatory T-cell response. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis. (Circulation. 2009; 120: 1996-2005.)
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2009, CIRCULATION, 120(20) (20), 1996 - U43, English
    Scientific journal

  • Plasma Tetrahydrobiopterin/Dihydrobiopterin Ratio - A Possible Marker of Endothelial Dysfunction
    Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Tomofumi Takaya, Kenji Nakajima, Nobutaka Inoue, Tomoya Masano, Hideto Tawa, Seimi Satomi-Kobayashi, Ryuji Toh, Daisuke Sugiyama, Kunihiro Nishimura, Mitsuhiro Yokoyama, Ken-ichi Hirata, Seinosuke Kawashima
    Background: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. Methods and Results: In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7,8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients with multiple coronary risk factors. There was a positive relationship between FMD and plasma BH4 levels and a negative relationship between FMD and plasma BH2 levels. Subsequently, a strong positive relationship between FMD and the BH4/BH2 ratio (r=0.585, P<0.0001) was found. Although we did not find any significant relationship between pteridine levels and individual traditional risk factors, the BH4/BH2 ratio in patients with more than 2 risk factors showed significant reductions compared with that in those without risk factors. Statin treatment improved FMD in association with oil increase in the plasma BH4/BH2 ratio. Conclusions: Plasma pteridine levels were associated with endothelial dysfunction in cardiovascular disorders. (Circ J 2009; 73: 955-962)
    JAPANESE CIRCULATION SOC, May 2009, CIRCULATION JOURNAL, 73(5) (5), 955 - 962, English
    [Refereed]
    Scientific journal

  • Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats - The possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase
    Tomoya Masano, Seinosuke Kawashima, Ryuji Toh, Seimi Satomi-Kobayashi, Masakazu Shinohara, Tornofumi Takaya, Naoto Sasaki, Masafumi Takeda, Hideto Tawa, Tomoya Yamashita, Mitsuhiro Yokoyama, Ken-ichi Hirata
    Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and Results Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function wits preserved compared with the control MI rats. Conclusions The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function.
    JAPANESE CIRCULATION SOC, Sep. 2008, CIRCULATION JOURNAL, 72(9) (9), 1512 - 1519, English
    [Refereed]
    Scientific journal

  • Naoto Sasaki, Tomoya Yamashita, Tomofumi Takaya, Masakazu Shinohara, Rio Shiraki, Masafumi Takeda, Noriaki Emoto, Akiko Fukatsu, Toshio Hayashi, Kazuhisa Ikemoto, Takahide Nomura, Mitsuhiro Yokoyama, Ken-ichi Hirata, Seinosuke Kawashima
    Objective-Diabetes mellitus is associated with increased oxidative stress, which induces oxidation of tetrahydrobiopterin (BH4) in vessel wall. Without enough BH4, eNOS is uncoupled to L-arginine and produces superoxide rather than NO. We examined the role of uncoupled eNOS in vascular remodeling in diabetes. Methods and Results-Diabetes mellitus was produced by streptozotocin in C57BL/6J mice. Under stable hyperglycemia, the common carotid artery was ligated, and neointimal formation was examined 4 weeks later. In diabetic mice, the neointimal area was dramatically augmented. This augmentation was associated with increased aortic superoxide formation, reduced aortic BH4/dihydrobiopterin (BH2) ratio, and decreased plasma nitrite and nitrate (NOx) levels compared with nondiabetic mice. Chronic BH4 treatment (10 mg/kg/d) reduced the neointimal area in association with suppressed superoxide production and inflammatory changes in vessels. BH4/BH2 ratio in vessel wall was preserved, and plasma NOx levels increased. Furthermore, in the presence of diabetes, overexpression of bovine eNOS resulted in augmentation of neointimal area, accompanied by increased superoxide production in the endothelium. Conclusions-In diabetes, increased oxidative stress by uncoupled NOSs, particularly eNOS, causes augmentation of vascular remodeling. These findings indicate restoration of eNOS coupling has an atheroprotective benefit in diabetes.
    LIPPINCOTT WILLIAMS & WILKINS, Jun. 2008, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 28(6) (6), 1068 - 1076, English
    [Refereed]
    Scientific journal

  • Masakazu Shinohara, Tomoya Yamashita, Hideto Tawa, Masafumi Takeda, Naoto Sasaki, Tomofumi Takaya, Ryuji Toh, Akihisa Takeuchi, Takuji Ohigashi, Kunio Shinohara, Seinosuke Kawashima, Mitsuhiro Yokoyama, Ken-Ichi Hirata, Atsushi Momose
    Reliable, non-invasive imaging modalities to characterize plaque components are clinically desirable for detecting unstable coronary plaques, which cause acute coronary syndrome. Although recent clinical developments in computed tomography (CT) have enabled the visualization of luminal narrowing and calcified plaques in coronary arteries, the identification of noncalcified plaque components remains difficult. Phase-contrast X-ray CT imaging has great potentials to reveal the structures inside biological soft tissues, because its sensitivity to light elements is almost 1,000 times greater than that of absorption-contrast X-ray imaging. Moreover, a specific mass density of tissue can be estimated using phase-contrast X-ray CT. Ex vivo phase-contrast X-ray CT was performed using a synchrotron radiation source (SPring-8, Japan) to investigate atherosclerotic plaque components of apolipoprotein E-deficient mice. Samples were also histologically analyzed. Phase-contrast X-ray CT at a spatial resolution of 10-20 mu m revealed atherosclerotic plaque components easily, and thin fibrous caps were detected. The specific mass densities of these plaque components were quantitatively estimated. The mass density of lipid area was significantly lower (1.011 +/- 0.001766 g/ml) than that of smooth muscle area or collagen area (1.057 +/- 0.001407 and 1.080 +/- 0.001794 g/ml, respectively). Moreover, the three-dimensional assessment of plaques could provide their anatomical information. Phase-contrast X-ray CT can estimate the tissue mass density of atherosclerotic plaques and detect lipid-rich areas. It can be a promising noninvasive technique for the investigation of plaque components and detection of unstable coronary plaques.
    AMER PHYSIOLOGICAL SOC, Feb. 2008, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 294(2) (2), H1094 - H1100, English
    [Refereed]
    Scientific journal

  • Masakazu Shinohara, Ken-ichi Hirata, Tomoya Yamashita, Tomofumi Takaya, Naoto Sasaki, Rio Shiraki, Tomomi Ueyama, Noriaki Emoto, Nobutaka Inoue, Mitsuhiro Yokoyama, Seinosuke Kawashima
    Objective-Atherosclerosis is now considered as a chronic inflammatory disease, and inflammation is closely related to immune systems, which consist of innate-immunity and adaptive-immunity. Recently, toll-like receptors (TLRs) have been identified as key components of innate-immunity. We examined the role of local expressions of TLRs at the vessel wall in atherosclerosis. Methods and Results-We transfected cDNA encoding human TLR2 and TLR4 into the carotid arterial vessel wall of rabbits fed high-cholesterol diets with the use of HVJ-liposome. The rabbits were transfected with (1) pCMV-beta-gal, (2) empty vector, (3) TLR2, (4) TLR4, (5) TLR2+4. X-gal staining and immunohistochemical analysis showed that the transfected plasmids were mainly expressed in the media. Neither TLR2 nor TLR4 transfection induced significant augmentation of atherosclerosis. Transfection of TLR2-and TLR4-containing HVJ synergistically accelerated atherosclerosis and increased expressions of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and MCP-1. Moreover, transfection of TLR2 and TLR4 resulted in synergistic activation of NF-kappa B at the vessel wall in vivo, and in vascular smooth muscle cells in vitro. Conclusions-Expressions of both TLR2 and TLR4 at the vessel wall synergistically accelerated atherosclerosis. The present study revealed the role of TLRs expressed locally at the vessel wall in the early stage of atherosclerosis.
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2007, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 27(11) (11), 2384 - 2391, English
    [Refereed]
    Scientific journal

  • Tomoya Yamashita, Seinosuke Kawashima, Tetsuaki Hirase, Masakazu Shinohara, Tomofumi Takaya, Naoto Sasaki, Masafumi Takeda, Hideto Tawa, Nobutaka Inoue, Ken-ichi Hirata, Mitsuhiro Yokoyama
    Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role, and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E knockout ( apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages ( phorbol ester-stimulated THP-1 cells), using human serum albumin as a control protein or HepG2 cells as human control cells, once a week for four consecutive weeks. The vehicle phosphate-buffered saline was injected in the nonimmunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. Although the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by >50% in 16-wk-old THP-1-immunized apoE-KO mice compared with that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the antiatherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis.
    AMER PHYSIOLOGICAL SOC, Sep. 2007, AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 293(3) (3), C865 - C873, English
    [Refereed]
    Scientific journal

  • Akihiro Matsui, Mitsuhiko Okigaki, Katsuya Amano, Yasushi Adachi, Denan Jin, Shinji Takai, Tomoya Yamashita, Seinosuke Kawashima, Tatsuya Kurihara, Mizuo Miyazaki, Kento Tateishi, Shinsaku Matsunaga, Asako Katsume, Shoken Honshou, Tomosaburo Takahashi, Satoaki Matoba, Tetsuro Kusaba, Tetsuya Tatsumi, Hiroaki Matsubara
    Background-The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined. Methods and Results-Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2(-/-) mice with reduced mobilization of endothelial progenitors. Vascular endothelial growth factor (VEGF)-mediated cytoplasmic Ca2+ mobilization and Ca2+- independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca2+- independent AMP-activated protein kinase/protein kinase-A pathway that phosphorylates endothelial NO synthase was not impaired. Acetylcholine-mediated aortic vasorelaxation and cGMP production were significantly decreased. Vascular endothelial growth factor-dependent migration, tube formation, and actin cytoskeletal reorganization associated with Rac1 activation were inhibited in PYK2-deficient endothelial cells. PI3-kinase is associated with vascular endothelial growth factor-induced PYK2/Src complex, and inhibition of Src blocked Akt activation. The vascular endothelial growth factor-mediated Src association with PLC gamma 1 and phosphorylation of (783)Tyr-PLC gamma 1 also were abolished by PYK2 deficiency. Conclusion-These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLC gamma 1 and Src/PI3- kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase-mediated vasoactive function and angiogenic response.
    LIPPINCOTT WILLIAMS & WILKINS, Aug. 2007, CIRCULATION, 116(9) (9), 1041 - 1051, English
    [Refereed]
    Scientific journal

  • Tomofumi Takaya, Ken-ichi Hirata, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Nobutaka Inoue, Toyotaka Yada, Masami Goto, Akiko Fukatsu, Toshio Hayashi, Nicholas J. Alp, Keith M. Channon, Mitsuhiro Yokoyama, Seinosuke Kawashima
    Objective - When the availability of tetrahydrobiopterin ( BH4) is deficient, endothelial nitric oxide synthase ( eNOS) produces superoxide rather than NO ( uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E - deficient ( ApoE- KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. Methods and Results - We crossed mice overexpressing eNOS in the endothelium ( eNOS- Tg) with mice overexpressing GTP- cyclohydrolase I ( GCH), the rate- limiting enzyme in BH4 synthesis, to generate ApoE- KO/ eNOS- Tg/ GCH- Tg mice. As a comparison, ApoE- KO/ eNOS- Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE- KO/ eNOS- Tg mice compared with ApoE- KO mice. GCH overexpression in ApoE- KO/ eNOS- Tg/ GCH- Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE- KO/ eNOS- Tg mice, despite reducing overall vascular superoxide production. Conclusion - In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE- KO/ eNOS- Tg mice, associated with a reduction of superoxide production from uncoupled eNOS.
    LIPPINCOTT WILLIAMS & WILKINS, Jul. 2007, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 27(7) (7), 1632 - 1637, English
    [Refereed]
    Scientific journal

  • Sho Yoshimura, Yoshihiro Nishimura, Teruaki Nishiuma, Tomoya Yamashita, Kazuyuki Kobayashi, Mitsuhiro Yokoyama
    Background: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown. Methods: eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally. Results: Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N-omega-nitro-L-arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions. Conclusion: These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance.
    BLACKWELL PUBLISHING, Sep. 2006, RESPIROLOGY, 11(5) (5), 546 - 556, English
    [Refereed]
    Scientific journal

  • Tomoya Yamashita, Stefan Freigang, Claudia Eberle, Jennifer Pattison, Sachin Gupta, Claudio Napoli, Wulf Palinski
    Maternal hypercholesterolemia during pregnancy increases offspring susceptibility to atherosclerosis by an oxidation-dependent mechanism. The present studies investigated whether maternal immunization with oxidized LDL ( OxLDL) before pregnancy protects the fetus from atherogenic in utero programming by maternal hypercholesterolemia. Maternal immunization of NZW rabbits and LDL receptor-deficient mice indeed reduced atherosclerosis in adult offspring by up to 56%, but the protective effect could not be attributed to a reduction of fetal exposure to hypercholesterolemia alone, and even nonspecific immune stimulation with adjuvant only provided some protection. Unexpectedly, offspring of immunized mothers developed increased IgM antibodies to selective OxLDL epitopes and increased IgM-LDL immune complexes, compared with offspring of nonimmunized controls. Even naive offspring of OxLDL-immunized mothers never exposed to postnatal hypercholesterolemia responded to a one-time OxLDL and KLH challenge with greater OxLDL-specific IgM responses, increased OxLDL-specific IgM-secreting B cells, and more IgM-LDL immune complexes. In contrast, maternal immunization with KLH, a T cell-dependent nonmammalian antigen, did not influence postnatal immune responses. Effects of maternal OxLDL-immunization on offspring B cells and selective antibodies were independent of transplacental passage of maternal immunoglobulins. Results show that maternal immunization with antigens prevalent in atherosclerotic lesions reduces atherogenesis in their offspring by mechanisms that include, but are not limited to, reduced fetal exposure to maternal hypercholesterolemia and lipid peroxidation. More importantly, they demonstrate in principle that maternal adaptive immunity to selective antigens influences postnatal B cell and antibody responses in offspring, and that modulation of in utero immune programming may influence immune-modulated diseases later in life.
    LIPPINCOTT WILLIAMS & WILKINS, Sep. 2006, CIRCULATION RESEARCH, 99(7) (7), E51 - E64, English
    [Refereed]
    Scientific journal

  • K Kobayashi, Y Nishimura, T Yamashita, T Nishiuma, M Satouchi, M Yokoyama
    The effects of nitric oxide (NO) on allergic inflammation are controversial. In particular, the role of endothelial nitric oxide synthase (eNOS) in asthma remains uncertain. In the present study, we examined the effects of overexpression of eNOS on allergic inflammation using eNOS transgenic (eNOS-Tg) mice, in which eNOS protein is overexpressed in the vascular endothelium and air-way epithelium. We found that eNOS-Tg mice showed a reduction of the asthmatic response to allergen challenge. Eosinophilic accumulation in the airspaces, eosinophilic activity, and bronchial responsiveness to acetylcholine were significantly attenuated in eNOS-Tg mice, as compared with wild-type mice following ovalbumin sensitization/challenge, even though the levels of circulating eosinophils were comparable in the wild-type and eNOS-Tg mice. The concentrations of eotaxin in the bronchoalveolar lavage fluid were significantly less in eNOS-Tg mice than in the wild-type mice. In addition, immunohistochemical analysis showed that the expressions of both intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on the pulmonary endothelium of eNOS-Tg mice was decreased compared with the controls. These results suggest that chronic cNOS overexpression contributes to the suppression of allergic inflammation by reducing the production of eotaxin in the airspaces and/or the expression of adhesion molecules in the vascular endothelium. (c) 2006 Elsevier B.V. All rights reserved.
    ELSEVIER SCIENCE BV, Jul. 2006, INTERNATIONAL IMMUNOPHARMACOLOGY, 6(7) (7), 1040 - 1052, English
    [Refereed]
    Scientific journal

  • K Takenaka, Y Nishimura, T Nishiuma, A Sakashita, T Yamashita, K Kobayashi, M Satouchi, T Ishida, S Kawashima, M Yokoyama
    Although mechanical ventilation (MV) is an important supportive strategy for patients with acute respiratory distress syndrome, MV itself can cause a type of acute lung damage termed ventilator-induced lung injury (VILI). Because nitric oxide (NO) has been reported to play roles in the pathogenesis of acute lung injury, the present study explores the effects on VILI of NO derived from chronically overexpressed endothelial nitric oxide synthase (eNOS). Anesthetized eNOS-transgenic (Tg) and wild-type (WT) C57BL/6 mice were ventilated at high or low tidal volume (V-T; 20 or 7 ml/kg, respectively) for 4 h. After MV, lung damage, including neutrophil infiltration, water leakage, and cytokine concentration in bronchoalveolar lavage fluid (BALF) and plasma, was evaluated. Some mice were given N-omega-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor, via drinking water (1 mg/ml) for 1 wk before MV. Histological analysis revealed that high VT ventilation caused severe VILI, whereas low VT ventilation caused minimal VILI. Under high VT conditions, neutrophil infiltration and lung water content were significantly attenuated in eNOS-Tg mice compared with WT animals. The concentrations of macrophage inflammatory protein-2 in BALF and plasma, as well as plasma tumor necrosis factor-alpha and monocyte chemoattractant protein-1, also were decreased in eNOS-Tg mice. L-NAME abrogated the beneficial effect of eNOS overexpression. In conclusion, chronic eNOS overexpression may protect the lung from VILI by inhibiting the production of inflammatory chemokines and cytokines that are associated with neutrophil infiltration into the air space.
    AMER PHYSIOLOGICAL SOC, Jun. 2006, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 290(6) (6), L1078 - L1086, English
    [Refereed]
    Scientific journal

  • T Takaya, S Kawashima, M Shinohara, T Yamashita, R Toh, N Sasaki, N Inoue, K Hirata, M Yokoyama
    Angiotensin 11 is involved in the process of atherosclerosis and stimulates superoxide production from cardiovascular cells. We examined the effect of telmisartan, an angiotensin 11 type I receptor blocker. on atherosclerosis. We chronically treated apolipoprotein E-deficient mice with two different doses of telmisartan dissolved in drinking water (0.3 and 3 mg/kg) starting from 4 weeks of age for 12 weeks. Lipid contents were not different in both telmisartan-treated groups compared with control group. Systolic blood pressure was significantly reduced with 3 mg/kg, but unchanged with 0.3 mg/kg. The total atherosclerotic lesion size at the aortic sinus was reduced with 0.3 mg/kg compared with control, and additional reduction was proved with 3 mg/kg. The fibrotic change was not different among three groups, but MOMA-2-, malondialdehyde-, 4-hydroxy-2-nonenal-immunostained areas were reduced by telmisartan. As the mechanism, we revealed that both doses of telmisartan markedly reduced superoxide production from in situ vessels assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining. And NAD(P)H dependent oxidase activity in vessels was reduced by telmisartan. Further, 8-iso-prostaglandin F2 alpha level, a systemic oxidative stress marker, obtained from urine and plasma samples were significantly reduced by telmisartan. Telmisartan reduced atherosclerosis in apolipoprotein E-deficient mice at least partly via the suppression of oxidative stress. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
    ELSEVIER IRELAND LTD, Jun. 2006, ATHEROSCLEROSIS, 186(2) (2), 402 - 410, English
    [Refereed]
    Scientific journal

  • R Toh, M Shinohara, T Takaya, T Yamashita, S Masuda, S Kawashima, M Yokoyama, N Yagi
    To investigate how beta-stimulation affects the contractility of cardiac muscle, x-ray diffraction from cardiac muscle in the left ventricular free wall of a mouse heart was recorded in vivo. To our knowledge, this is the first x-ray diffraction study on a heart in a living body. After the R wave in electrocardiograms, the ratio of the intensities of the equatorial (1,0) and (1,1) reflections decreased for similar to 50 ms from a diastolic value of 2.1 to a minimum of 0.8, and then recovered. The spacing of the (1,0) lattice planes increased for; 90 ms from a diastolic value of 37.2 nm to a maximum of 39.1 nm, and then returned to the diastolic level, corresponding to similar to 10% stretch of sarcomere. Stimulation of beta-adrenergic receptor by dobutamine (20 mu g/kg/min) accelerated both the decrease in the intensity ratio, which reached a smaller systolic value, and the increase in the lattice spacing. However, the intensity ratio and spacing at the end-diastole were unchanged. The recovery of the lattice spacing during relaxation was also accelerated. The mass transfer to the thin. laments at systole in a beta-stimulated heart was close to the peak value in twitch of frog skeletal muscle at 4 degrees C, showing that the majority of cross-bridges have been recruited with few in reserve.
    BIOPHYSICAL SOCIETY, Mar. 2006, BIOPHYSICAL JOURNAL, 90(5) (5), 1723 - 1728, English
    [Refereed]
    Scientific journal

  • M Shinohara, S Kawashima, T Yamashita, T Takaya, R Toh, T Ishida, T Ueyama, N Inoue, KI Hirata, M Yokoyama
    Objective: Intimal hyperplasia plays an important role in a variety of types of vascular remodeling, particularly luminal narrowing after vascular injury. The vascular smooth muscle cells (VSMCs) in the neointimal area are a synthetic phenotype and have different epitopes from VSMCs in the normal media. The synthetic VSMCs in the neointima contain various possible antigens that can be targeted by the immune system. In this study, we tried to develop a new immumotherapy, which targets the synthetic VSMCs, for prevention of neointimal formation after angioplasty. Method and results: Rabbits were repeatedly immunized with fixed xenogenic rat cultured VSMCs suspended in adjuvant as immumogens or injected with adjuvant and phosphate-buffered saline (PBS) or rat hepatocytes as controls every 2 weeks for 3 times. One week after the last immunization/injection, balloon injury of the left common carotid artery was performed. Four weeks after the injury, rabbits were euthanized and the neointimal lesion formation was assessed. The mean neointimal area of the PBS-injected, non-immunized group and the rat hepatocyte-immunized, control group was not statistically different (0.339 +/- 0.036 and 0.350 +/- 0.041 mm, P=NS). However, immunization with rat VSMCs significantly reduced the intimal lesion area (0.219 +/- 0.0286 mm(2); P < 0.05 vs. PBS-injected, non-immunized group and rat hepatocyte-immunized group.) PCNA-immunopositive proliferating VSMCs in the neointima, were suppressed by the rat VSMC immunization (1.34 +/- 0.49% vs. 5.78 +/- 0.47%; P < 0.05 vs. PBS-injected, non-immunized group). Rat VSMC immunization induced antibodies which had strong cross-reactivity against rabbit synthetic VSMCs. In experiments in vitro, proliferation and migration of rabbit VSMCs that were stimulated by serum, angiotensin (AT) II, platelet-derived growth factor (PDGF)-BB, fibroblast growth factor (FGF), and the phorbol ester PMA were significantly suppressed by treatment with immunoglobulin extracted from the VSMC-immunized rabbit plasma, implying that the immunoglobulin had some global effects on VSMCs. The rat VSMC-immunized rabbit immunoglobulin bound the rabbit AT1a receptor protein, which was expressed in COS7 cells by transfection of rabbit AT1a receptor pcDNA3. This binding to AT1a receptor may be one of mechanisms of the effects of VSMC-immunized immumoglobulin. Conclusion: Xenogenic, synthetic rat VSMC immunization in rabbits induced auto-antibodies against synthetic rabbit VSMCs in a crossreaction. The induced auto-antibodies against synthetic VSMCs may provide a possibility of new immunotherapy for vascular remodeling that forms neointimal lesions. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
    ELSEVIER SCIENCE BV, Nov. 2005, CARDIOVASCULAR RESEARCH, 68(2) (2), 249 - 258, English
    Scientific journal

  • T Ishida, SSY Choi, RK Kundu, J Spin, T Yamashita, K Hirata, Y Kojima, M Yokoyama, AD Cooper, T Quertermous
    Endothelial lipase (EL) expression correlates inversely with circulating high density lipoprotein (HDL) cholesterol levels in genetic mouse models, and human genetic variation in this locus has been linked to differences in HDL cholesterol levels. These data suggest a role for EL in the development of atherosclerotic vascular disease. To investigate this possibility, LIPG-null alleles were bred onto the apoE knockout background, and the homozygous double knockout animals were characterized. Both apoE knockout and double knockout mice had low HDL cholesterol levels when compared with wild-type mice, but the HDL cholesterol levels of the double knockout mice were higher than those of apoE knockout mice. Atherogenic very low density lipoprotein and intermediate density lipoprotein/low density lipoprotein cholesterol levels of the double knockout mice were also greater than those of the apoE knockout animals. Despite this lipid profile, there was a significant similar to 70% decrease in atherosclerotic disease area in double knockout mice on a regular diet. Immunohistochemistry and protein blot studies revealed increased EL expression in the atherosclerotic aortas of the apoE knockout animals. An observed decrease in macrophage content in vessels lacking EL correlated with ex vivo vascular monocyte adhesion assays, suggesting that this protein can modulate monocyte adhesion and infiltration into diseased tissues. These data suggest that EL may have indirect atherogenic actions in vivo through its effect on circulating HDL cholesterol and direct atherogenic actions through vascular wall processes such as monocyte recruitment and cholesterol uptake.
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Oct. 2004, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(43) (43), 45085 - 45092, English
    [Refereed]
    Scientific journal

  • M Namiki, S Kawashima, T Yamashita, M Ozaki, T Sakoda, N Inoue, KI Hirata, R Morishita, Y Kaneda, M Yokoama
    Atherosclerosis has a close relationship to inflammation, particularly T helper type 1 lymphocyte (Th1) response. Interleukin-10 (IL-10), is thought to suppress Th1 response. To target therapeutic strategy for atherosclerosis, we tested whether IL-10 gene transfer suppresses atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. Four-week-old apoE-KO mice were divided into two groups and either murine IL-10 cDNA plasmid or empty control vector was transferred to the femoral muscle with the use of Hemagglutinating virus of Japan (HVJ)-tiposome. At 1 week after transfection, high cholesterol diet was started and continued for 8 weeks. After euthanasia, histological studies of atherosclerotic lesions and quantitative RT-PCR for Th1 cytokines (IL-12 and IFN-gamma) in spleens were performed. IL-10 cDNA gene transfer to the muscle increased plasma IL-10 levels and depressed expression of Th1 cytokines without changing plasma cholesterol levels. IL-10 gene transfer significantly reduced the atherosclerotic plaque area and the macrophage infiltrated area. IL-12 and IFN-gamma mRNA expressions in spleens and plasma IFN-gamma levels were decreased by IL-10 gene transfer. Therefore, IL-10 gene transfer changed the Th1 response and suppressed atherosclerotic lesion formation in apoE-KO mice. IL-10 could be a new target as a therapeutic tool for the treatment of atherosclerosis. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
    ELSEVIER SCI IRELAND LTD, Jan. 2004, ATHEROSCLEROSIS, 172(1) (1), 21 - 29, English
    [Refereed]
    Scientific journal

  • 異種血管平滑筋細胞を用いた免疫誘導療法による再狭窄の防止
    篠原正和, KAWASHIMA, Seinosuke, 高谷具史, YAMASHITA,Tomoya, INOUE,Nobutaka, HIRATA, Kenichi, YOKOYAMA, Mitsuhiro
    Sep. 2003, 日本動脈硬化学会総会プログラム・抄録集, pp. 211-211, Japanese
    International conference proceedings

  • S Kawashima, T Yamashita, Y Miwa, M Ozaki, M Namiki, T Hirase, N Inoue, K Hirata, M Yokoyama
    Background and Purpose-Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur. Methods-We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed. Results-At 14 weeks of age, the incidence (13 +/- 3% versus 37 +/- 8%; P<0.01) and the size of stroke (1.6 +/- 0.2 versus 2.2 +/- 0.1 arbitrary units; P<0.01) were significantly decreased by cerivastatin, although blood pressure and plasma cholesterol levels were not different. Moreover, stroke-associated symptoms and early mortality of SHR-SP were markedly reduced in the statin-treated group (mortality at the age of 15 weeks: 15% versus 50%; P<0.05). Statin treatment significantly reduced superoxide production from nonstroke parenchyma of brain and infiltration of inflammatory cells to the stroke lesions. Conclusions-Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.
    LIPPINCOTT WILLIAMS & WILKINS, Jan. 2003, STROKE, 34(1) (1), 157 - 163, English
    [Refereed]
    Scientific journal

  • A 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor reduces hypertensive nephrosclerosis in stroke-prone spontaneously hypertensive rats
    T Yamashita, S Kawashima, Y Miwa, M Ozaki, M Namiki, T Hirase, N Inoue, K Hirata, M Yokoyama
    Background Recent studies suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) exert their protective effects against cardiovascular diseases independently of their cholesterol-decreasing effects. Objective To clarify the effect of a statin on hypertensive nephrosclerosis. Methods We treated stroke-prone spontaneously hypertensive rats (spSHRs) chronically, starting at the age of 4 weeks, with cerivastatin (2 mg/kg per day by gavage) or vehicle. Physiological parameters, plasma chemistry and urine protein excretion were analysed. At 14 weeks of age, the rats had their kidneys removed for use in assays. Results Compared with vehicle treatment, statin treatment reduced proteinuria and renal injury independently of blood pressure and cholesterol concentrations in spSHRs. Although expression of adhesion molecules and infiltration of inflammatory cells were not different whether or not cerivastatin treatment was used, renal fibrosis was significantly reduced in statin-treated spSHRs. We also found that expression of transforming growth factor-beta1 in kidneys was significantly inhibited in statin-treated spSHRs. Conclusion Cerivastatin prevents or retards hypertension-induced renal injury via inhibition of renal fibrosis and proteinuria. These results show the potential of statins as protective tools against proteinuric renal diseases, independent of their cholesterol-decreasing effects. (C) 2002 Lippincott Williams Wilkins.
    LIPPINCOTT WILLIAMS & WILKINS, Dec. 2002, JOURNAL OF HYPERTENSION, 20(12) (12), 2465 - 2473, English
    [Refereed]
    Scientific journal

  • Y Rikitake, K Hirata, T Yamashita, K Iwai, S Kobayashi, H Itoh, M Ozaki, J Ejiri, M Shiomi, N Inoue, S Kawashima, M Yokoyama
    Objective-Lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low density lipoprotein, has been demonstrated to induce multiple functional alterations of vasculature that are potentially involved in atherosclerosis. Recently, an orphan G-protein- coupled receptor, G2A, has been identified as a high-affinity receptor for LPC. Although it has been demonstrated that G2A is expressed predominantly in lymphoid tissues and lymphocytes, there are no reports to determine whether G2A is expressed in atherosclerotic lesions and cardiovascular cells. Methods and Results-Immunohistochemistry with an anti-G2A antibody revealed that G2A was expressed predominantly by macrophages within atherosclerotic lesions at the aortic root of apolipoprotein E-deficient mice and the thoracic aortas of Watanabe heritable hyperlipidemic rabbits. In atherosclerotic plaques of human coronary arterial specimens, G2A was expressed by macrophages within the lipid-rich plaques, whereas no immunoreactivity of G2A was observed in fibrous plaques where macrophages did not exist. Reverse transcription-polymerase chain reaction analysis demonstrated that G2A mRNA was highly expressed in human and murine monocytes/macrophages. The expression of G2A protein was detected in human and murine monocytes/macrophages by immunoblotting. Conclusions-These findings demonstrate that monodytes/macrophages abundantly express G2A and suggest that G2A may play a role in the formation and progression of atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 2002;22: 2049-2053.).
    LIPPINCOTT WILLIAMS & WILKINS, Dec. 2002, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(12) (12), 2049 - 2053, English
    [Refereed]
    Scientific journal

  • In vivo angiographic detection of vascular lesions in apolipoprotein E-knockout mice using a synchrotron radiation microangiography system
    T Yamashita, S Kawashima, M Ozaki, M Namiki, M Shinohara, N Inoue, K Hirata, K Umetani, M Yokoyama
    Genetically modified hyperlipidemic mice provide important information on the pathogenesis of atherosclerosis, but most experimental designs are limited to in vitro or ex vivo examinations. The present study was designed to detect atherosclerotic lesions in situ in apolipoprotein E-knockout (apoE-KO) mice using a newly developed angiography system, synchrotron radiation (SR) microangiography, which uses monochromatic SR as an X-ray source and a high definition camera or video system as a detector. Digital microangiography with 7 mm pixel sizes was carried out and atherosclerotic lesion in small arteries less than 500 mum in diameter were detected. Moreover, the coronary artery stenotic lesion of an apoE-KO mouse was detected in situ with the angiography system. The new SR microangiography system is a powerful tool for investigating atherosclerotic lesions in situ in genetically engineered mice and will promote the basic study of atherosclerotic disease.
    BLACKWELL PUBLISHING ASIA, Nov. 2002, CIRCULATION JOURNAL, 66(11) (11), 1057 - 1059, English
    [Refereed]
    Scientific journal

  • Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion
    M Ozaki, S Kawashima, T Yamashita, T Hirase, Y Ohashi, N Inoue, K Hirata, M Yokoyama
    Endogenous nitric oxide (NO) inhibits the contractile response to beta-adrenergic stimulation, but its effect on cardiac hypertrophy mediated by f-adrenoceptors remains unclear. The present study was designed to determine whether overproduction of endothelial NO synthase (eNOS) could inhibit cardiac hypertrophy induced by chronic isoproterenol (ISO) infusion (30mg/kg per day) using eNOS overexpressing (eNOS-Tg) mice and wild-type (WT) mice. In a separate group, WT mice were treated with ISO and hydralazine to decrease blood pressure to the same levels in eNOS-Tg mice. The eNOS expression, NOS activity, and cGMP levels in the heart were remarkably higher in eNOS-Tg mice than in WT mice. ISO increased both heart weight and the heart/body weight ratio, which were significantly attenuated in eNOS-Tg mice compared with WT or hydralazine-treated WT mice. Histological examination revealed that the extent of fibrosis was not significantly different among the 3 groups, and that the increase in myocyte size was more than 10% lower in eNOS-Tg than in the other groups. In addition, up-regulated expression of atrial natriuretic peptide mRNA associated with cardiac hypertrophy was significantly inhibited in eNOS-Tg mice during ISO infusion. These results indicate that endogenous NO might act as a negative modulator for the hypertrophic response to beta-adrenergic stimulation.
    BLACKWELL PUBLISHING ASIA, Sep. 2002, CIRCULATION JOURNAL, 66(9) (9), 851 - 856, English
    [Refereed]
    Scientific journal

  • T Yamashita, S Kawashima, M Ozaki, M Namiki, N Inoue, K Hirata, M Yokoyama
    Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte, infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62 +/- 0.12 versus 1.27 +/- 0.07 mm(2), respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23 +/- 0.06 mm(2) [drug-treated group] versus 0.67 +/- 0.07 mm(2) [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.
    LIPPINCOTT WILLIAMS & WILKINS, Jun. 2002, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(6) (6), 969 - 974, English
    [Refereed]
    Scientific journal

  • Overexpression of endothelial nitric oxide synthase in endothelial cells is protective against ischemia-reperfusion injury in mouse skeletal muscle
    M Ozaki, S Kawashima, T Hirase, T Yamashita, M Namiki, N Inoue, K Hirata, M Yokoyama
    Microvascular injury has been proposed to be a main cause of ischemia-reperfusion (I/R) injury. The roles of endothelial nitric oxide synthase (eNOS)-derived NO, a key regulator of vascular function, in I/R injury are incompletely understood. We used transgenic mice overexpressing eNOS in endothelial cells (eNOS-Tg) and their littermates wild-type mice (WT) to investigate the roles of eNOS in I/R injury in skeletal muscle. Superoxide levels in the affected muscles were reduced by approximately 50% in eNOS-Tg compared with WT during reperfusion. In WT, the disassembly of endothelial junctional proteins seen in the early period of reperfusion was recovered in the later phase. These findings were correlated with the increased vascular permeability in vivo. In contrast, eNOS-Tg maintained the endothelial junction assembly as well as vascular permeability during reperfusion. Leukocyte extravasation into tissue and up-regulated expression of adhesion molecules in the reperfused vessels were significantly inhibited in eNOS-Tg. Tissue viability of the affected muscle was decreased in WT time-dependently after reperfusion, whereas eNOS-Tg showed no significant reduction. NOS inhibition completely reversed these protective effects of eNOS overexpression in I/R injury. Thus, eNOS overexpression appears to prevent the I/R injury in skeletal muscle by maintaining vascular integrity.
    AMER SOC INVESTIGATIVE PATHOLOGY, INC, Apr. 2002, AMERICAN JOURNAL OF PATHOLOGY, 160(4) (4), 1335 - 1344, English
    [Refereed]
    Scientific journal

  • Masanori Ozaki, Seinosuke Kawashima, Tomoya Yamashita, Tetsuaki Hirase, Masayuki Namiki, Nobutaka Inoue, Ken-Ichi Hirata, Hiroyuki Yasui, Hiromu Sakurai, Yuichi Yoshida, Masahiro Masada, Mitsuhiro Yokoyama
    Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. Therefore, augmentation of eNOS expression or NO production by pharmacological intervention is postulated to inhibit atherosclerosis. We crossed eNOS-overexpressing (eNOS-Tg) mice with atherogenic apoE-deficient (apoE-KO) mice to determine whether eNOS overexpression in the endothelium could inhibit the development of atherosclerosis. After 8 weeks on a high-cholesterol diet, the atherosclerotic lesion areas in the aortic sinus were unexpectedly increased by more than twofold in apoE-KO/eNOS-Tg mice compared with apoE-KO mice. Also, aortic tree lesion areas were approximately 50% larger in apoE-KO/eNOS-Tg mice after 12 weeks on a high-cholesterol diet. Expression of eNOS and NO production in aortas from apoE-KO/eNOS-Tg mice were significantly higher than those in apoE-KO mice. However, eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, was observed in apoE-KO/eNOS-Tg mice. Supplementation with tetrahydrobiopterin, an NOS cofactor, reduced the atherosclerotic lesion size in apoE-KO/eNOS-Tg mice to the level comparable to apoE-KO mice, possibly through the improvement of eNOS dysfunction. These data demonstrate that chronic overexpression of eNOS does not inhibit, but accelerates, atherosclerosis under hypercholesterolemia and that eNOS dysfunction appears to play important roles in the progression of atherosclerosis in apoE-KO/eNOS-Tg mice.
    The American Society for Clinical Investigation, 2002, Journal of Clinical Investigation, 110(3) (3), 331 - 340, English
    Scientific journal

  • M Namiki, S Kawashima, T Yamashita, M Ozaki, T Hirase, T Ishida, N Inoue, K Hirata, A Matsukawa, R Morishita, Y Kaneda, M Yokoyama
    Monocyte/macrophage infiltration to the arterial wall is an initial step in atherosclerosis, and monocyte chemoattractant protein-1 (MCP-1) is thought to play a central role in the recruitment of these cells. In the present study, we examined the role of local expression of MCP-1 at the vessel wall in the initiation and development of atherosclerosis. We transfected the cDNA encoding rat MCP-1 into the vessel wall of the rabbit carotid artery with the use of the hemagglutinating virus of Japan (HVJ)-liposome method. The rabbits were divided into the following groups: (1) those fed normal chow and transfected with MCP-1-HVJ, (2) those fed a high cholesterol diet (1% cholesterol) and transfected with MCP-1-HVJ, and (3) those fed a high cholesterol diet and transfected with control-HVJ. Prescribed diets were started 2 weeks before transfection and were continued for another 2 weeks. In group I, vascular lesion formation was not found, and anti-rabbit monocyte/macrophage antibody (RAM-11) staining for monocytes/macrophages was negative, although anti-rat MCP-1 antibody (R-17) staining for rat MCP-1 was positive mainly in endothelial cells. Cholesterol feeding increased plasma cholesterol levels to 1801+/-444 mg/dL in group 2. In group 2, all rabbits displayed neointimal formation with infiltration of RAM-11-positive cells, and a part of the lesion was also positive for Sudan III lipid staining. In group 3, hypercholesterolemia did not induce the infiltration of monocytes/ macrophages and subsequent lesion formation in the vessel wall despite definite upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on the endothelium. To initiate atherosclerotic changes, local MCP-1 overexpression at the vessel is not sufficient, and activation of other factors induced by hypercholesterolemia is required.
    LIPPINCOTT WILLIAMS & WILKINS, Jan. 2002, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(1) (1), 115 - 120, English
    [Refereed]
    Scientific journal

  • T Yamashita, S Kawashima, M Ozaki, M Namiki, S Satomi-Kobayashi, T Seno, Y Matsuda, N Inoue, K Hirata, H Akita, K Umetani, E Tanaka, H Mori, M Yokoyama
    Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a central role in regulation of vascular tone and reactivity. The purpose of this study is to clarify the basal tone and microvascular reactivity in eNOS-overexpressing transgenic (Tg) mice in vivo with a microangiography system using monochromatic synchrotron radiation (SR). The mouse femoral artery was cannulated, nonionic contrast media was injected, and microangiography was performed in hindlimbs of mice. Serial images of the small blood vessels (diameter < 200 mum) were recorded by the SR microangiography system. At basal conditions, the diameter of tibial arteries in eNOS-Tg mice was larger than that of wild-type mice (179 +/- 8 versus 132 +/- 8 pm; P < 0.01). L-NAME treatment decreased the vessel diameter and canceled the difference in vessel diameters between two genotypes. Acetylcholine- and sodium nitroprusside-induced relaxations of small vessels were significantly reduced in Tg mice compared with wild-type mice (35.0 +/- 9.4 versus 61.6 +/- 6.7%, 85.0 +/- 10.2 versus 97.3 +/- 6.7% of the maximum relaxation, respectively). Our data provide the evidence that overproduced NO from endothelium reduces vascular tone and plays a pivotal role in regulation of vascular tone in small vessels. Furthermore, the reduced NO-mediated relaxation in small vessels of eNOS-Tg mice is demonstrated for the first time in vivo. SR microangiography allows us to evaluate the reactivity in small-sized vessels and appears to be a powerful tool for assessing the microvascular circulation in vivo. (C) 2001 Academic Press.
    ACADEMIC PRESS INC, Oct. 2001, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 5(5) (5), 494 - 503, English
    [Refereed]
    Scientific journal

  • A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide production
    T Yamashita, S Kawashima, M Ozaki, Y Rikitake, T Hirase, N Inoue, K Hirata, M Yokoyama
    Objective Recent studies suggest that several calcium channel blockers exert their protective effects against vascular disorders by increasing nitric oxide (NO) production from the endothelium, The purpose of this study was to clarify the effects of a long-lasting calcium channel blocker, benidipine, on vascular remodeling. Methods The left common carotid arteries of mice were completely ligated just proximal to the carotid bifurcation. Treatment with benidipine (3 mg/kg per day) or vehicle was started 1 week before the carotid ligation, and continued throughout the experiments. Four weeks after the carotid ligation, these mice were killed and vascular remodeling was analyzed. Moreover, NO production and endothelial NO synthase (eNOS) expression were assessed. Results At 4 weeks after ligation, the neointimal area in the vehicle-treated mice was 39 400 +/- 4900 mum(2) (n = 8), whereas that in the drug-treated mice was reduced to 18 300 +/- 3800 mum(2) (n = 10), Consequently, the luminal area was 35% larger in the drug-treated mice. Benidipine increased the basal as well as agonist-induced NO production from the endothelium, detected by Griess method or NOx analyzer. Endothelial NOS expression in vessels of the drug-treated mice was increased compared with that of the vehicle-treated mice. Conclusion Our data provide evidence that benidipine increases NO production via increment of eNOS protein in vessels and prevents intimal thickening in mice. These results show the possibility of benidipine as a protective tool against vascular remodeling independent of its effect on blood pressure. I Hypertens 19:451-458 (C) 2001 Lippincott Williams & Wilkins.
    LIPPINCOTT WILLIAMS & WILKINS, Mar. 2001, JOURNAL OF HYPERTENSION, 19(3) (3), 451 - 458, English
    [Refereed]
    Scientific journal

  • Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium
    M Ozaki, S Kawashima, T Yamashita, Y Ohashi, Y Rikitake, N Inoue, K Hirata, Y Hayashi, H Itoh, M Yokoyama
    We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca2+-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype, Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice, Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 <mu>m) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice, Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.
    LIPPINCOTT WILLIAMS & WILKINS, Feb. 2001, HYPERTENSION, 37(2) (2), 322 - 327, English
    [Refereed]
    Scientific journal

  • Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodeling
    S Kawashima, T Yamashita, M Ozaki, Y Ohashi, H Azumi, N Inoue, K Hirata, Y Hayashi, H Itoh, M Yokoyama
    NO produced by endothelial NO synthase (eNOS) plays important roles in the regulation of vascular tone and structure. The purpose of this study was to clarify the role of eNOS-derived NO on vascular remodeling by use of eNOS-transgenic (eNOS-Tg) mice. The common carotid artery was ligated just proximal to the carotid bifurcation. Four weeks later, the proximal carotid artery of the ligation site was histologically examined. In this vascular remodeling model, the endothelium remains uninjured, but neointimal and medial thickening occurs in combination with a reduction in vascular diameter at the proximal portion of the ligation. At 4 weeks after ligation, the respective neointimal and medial areas in wild-type mice were 17 200 +/- 1100 and 24 300 +/- 1500 mum(2), whereas both were reduced to 8000 +/- 1900 (P<0.01) and 18 400<plus/minus>700 mum(2) (P<0.01) in eNOS-Tg mice (n=8). Total vascular area was not different between the 2 genotypes. N-G-Nitro-L-arginine methyl ester treatment increased neointimal and medial areas to the same extent in both genotypes. Leukocyte infiltration was observed in the luminal side of the vessel, but the number of infiltrating cells was significantly attenuated in eNOS-Tg mice compared with wild-type mice. This reduction of leukocyte infiltration in eNOS-Tg mice was associated with reduced expressions of intracellular adhesion molecule-1 and vascular cellular adhesion molecule-1 on the endothelium, In conclusion, chronic eNOS overexpression in the endothelium reduced leukocyte infiltration and inhibited neointimal formation and medial thickening. Our data provide the evidence for the regulatory role of NO from the endothelium on vascular structure integrity.
    LIPPINCOTT WILLIAMS & WILKINS, Feb. 2001, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 21(2) (2), 201 - 207, English
    [Refereed]
    Scientific journal

  • Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits
    Y Rikitake, S Kawashima, S Takeshita, T Yamashita, H Azumi, N Yasuhara, H Nishi, N Inoue, M Yokoyama
    Studies in vitro reveal that fluvastatin, an HMG-CoA reductase inhibitor, has a strong DPPH radical scavenging activity and achieves concentration-dependent inhibition of copper- and cell-induced oxidation of low-density lipoprotein (LDL). To further examine the anti-oxidative activity of fluvastatin in vivo, we elucidated the effects of chronic treatment with fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on vasomotion and vascular oxidative stress in thoracic aortas of 0.5% cholesterol-fed rabbits. After 12 weeks of dietary treatment, aortic segments from rabbits fed cholesterol alone showed impaired endothelium-dependent relaxation responses to acetylcholine and A23187 compared to normal chow-fed rabbits in association with a significant increase in plasma total cholesterol levels. In contrast, although plasma total cholesterol levels were not different from those in control cholesterol-fed rabbits, aortic segments from fluvastatin-treated rabbits showed normal relaxation. Compared with rabbits fed cholesterol alone, fluvastatin treatment decreased susceptibility of LDL to ex vivo copper-induced oxidation, reduced vascular superoxide generation, and atheromatous plaque formation. In conclusion, the potent anti-oxidative properties of fluvastatin in addition to its cholesterol-lowering activity appear to contribute to its anti-atherosclerotic effect in vivo. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
    ELSEVIER SCI IRELAND LTD, Jan. 2001, ATHEROSCLEROSIS, 154(1) (1), 87 - 96, English
    [Refereed]
    Scientific journal

  • Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase
    T Yamashita, S Kawashima, Y Ohashi, M Ozaki, Y Rikitake, N Inoue, K Hirata, H Akita, M Yokoyama
    NO, constitutively produced by endothelial NO synthase (eNOS), plays a key regulatory role in vascular wall homeostasis. We generated transgenic (Tg) mice overexpressing eNOS in the endothelium and reported the presence of reduced NO-elicited relaxation. The purpose of this study was to clarify mechanisms of the reduced response to NO-mediated vasodilators in eNOS-Tg mice. Thoracic aortas of Tg and control mice were surgically isolated for vasomotor studies. Relaxations to acetylcholine and sodium nitroprusside were significantly reduced in Tg vessels compared with control vessels. Relaxations to atrial natriuretic peptide and 8-bromo-cGMP were also significantly reduced in Tg vessels. Reduced relaxations to these agents were restored by chronic N-G-nitro-L-arginine methyl ester treatment, Basal cGMP levels of aortas were higher in Tg mice than in control mice, whereas soluble guanylate cyclase (sGC) activity in Tg vessels was approximate to 50% of the activity in control vessels. Moreover, cGMP-dependent protein kinase (PKG) protein levels and PKG enzyme activity were decreased in Tg vessels. These observations indicate that chronic overexpression of cNOS in the endothelium resulted in resistance to the NO/cCMP-mediated vasodilators and that at least 2 distinct mechanisms might be involved: one is reduced sGC activity, and the other is a decrease in PKG protein levels. We reported for the first time that increased NO release from the endothelium reduces sGC and PKG activity in mice. These data may provide a new insight into the mechanisms of nitrate tolerance and cross tolerance to nitrovasodilators.
    LIPPINCOTT WILLIAMS & WILKINS, Jul. 2000, HYPERTENSION, 36(1) (1), 97 - 102, English
    [Refereed]
    Scientific journal

  • T Ueyama, S Kawashima, T Sakoda, Y Rikitake, T Ishida, M Kawai, T Yamashita, S Ishido, H Hotta, M Yokoyama
    The signal transduction mechanisms mediating hypertrophic responses in myocardial cells (MCs) remain uncertain. We investigated the role of the extracellular signal-regulated kinase (ERK) cascade in myocardial cell hypertrophy by the strategy of using the adenovirus-mediated overexpression of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), which is the upstream activator of ERK. We generated recombinant adenoviruses expressing constitutively active MEK1 (MEK1 EE) and dominant negative MEK1 (MEK1 DN). Overexpression of MEK1 EE in MCs activated ERK1/2 and subsequently induced atrial natriuretic peptide (ANP) mRNA expression. In addition, MEK1 EE overexpression resulted in an increase in cell size and sarcomeric reorganization, rn contrast, overexpression of MEK1 DN in MCs inhibited endothelin-1 (ET-1)-, phenylephrine (PE)-, leukemia inhibitory factor (LIF)-, isoproterenol (ISP)-, and mechanical stretch-induced ERK activation and ANP mRNA expression. MEK1 DN overexpression inhibited ET-1-, PE-, LIF-, and ISP-induced increases in cell size and sarcomeric reorganization. Consistent with the observed effects on cellular morphology, overexpression of MEK1 EE resulted in an increase in amino acid incorporation, while overexpression of MEK1 DN inhibited ET-1-, PE-. LIF-, ISP-, and mechanical stretch-induced increases in amino acid incorporation. These results indicate that the ERK cascade plays an important role in the signaling pathway leading to the development of myocardial cell hypertrophy. (C) 2000 Academic Press.
    ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Jun. 2000, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 32(6) (6), 947 - 960, English
    [Refereed]
    Scientific journal

  • Y Rikitake, S Kawashima, T Yamashita, T Ueyama, S Ishido, H Hotta, K Hirata, M Yokoyama
    Lysophosphatidylcholine (lysoPC), a major lipid component of oxidized low density lipoprotein, inhibits endothelial cell. (EC) migration and proliferation, which are critical processes during angiogenesis and the repair of injured vessels. However, the mechanism(s) of lysoPC-induced inhibition of EC migration and proliferation has not been clarified, in this report, we demonstrate the critical role of extracellular signal-regulated kinase (ERK) in growth factor-stimulated EC migration and proliferation as well as their inhibition by lysoPC. EC migration and proliferation stimulated by basic fibroblast growth factor (FGF-2) were blocked by inhibition of ERK activity by both the specific mitogen-activated protein kinase kinase (MEK) 1 inhibitor PD98059 and the overexpression of a dominant-negative mutant of MEK1, Conversely, overexpression of a constitutively active mutant of MEK1 increased EC migration and proliferation, which were comparable to those of ECs stimulated with FGF-2. LysoPC inhibited FGF-2-induced ERK activation via prevention of Ras activation without inhibiting tyrosine phosphorylation of phospholipase C-gamma. Taken together, our data demonstrate that ERK activity is required for FGF-2-induced EC migration and proliferation and suggest that inhibition of the Ras/ERK pathway by lysoPC contributes to the reduced EC migration and proliferation.
    LIPPINCOTT WILLIAMS & WILKINS, Apr. 2000, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 20(4) (4), 1006 - 1012, English
    [Refereed]
    Scientific journal

  • Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase
    T Yamashita, S Kawashima, Y Ohashi, M Ozaki, T Ueyama, T Ishida, N Inoue, K Hirata, H Akita, M Yokoyama
    Background-Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice. Methods and Results-LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97 +/- 3 to 59 +/- 3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84 +/- 4 to 71 +/- 4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in TG mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in TG mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice. Conclusions-Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
    LIPPINCOTT WILLIAMS & WILKINS, Feb. 2000, CIRCULATION, 101(8) (8), 931 - 937, English
    [Refereed]
    Scientific journal

  • Yoshitaka Ohashi, Seinosuke Kawashima, Ken-Ichi Hirata, Tomoya Yamashita, Tatsuro Ishida, Nobutaka Inoue, Tsuyoshi Sakoda, Hiroki Kurihara, Yoshio Yazaki, Mitsuhiro Yokoyama
    Nitric oxide (NO), constitutively produced by endothelial nitric oxide synthase (eNOS), plays a major role in the regulation of blood pressure and vascular tone. We generated transgenic mice overexpressing bovine eNOS in the vascular wall using murine preproendothelin-1 promoter. In transgenic lineages with three to eight transgene copies, bovine eNOS-specific mRNA, protein expression in the particulate fractions, and calcium-dependent NOS activity were confirmed by RNase protection assay, immunoblotting, and L- arginine/citrulline conversion. Immunohistochemical studies revealed that eNOS protein was predominantly localized in the endothelial cells of aorta, heart, and lung. Blood pressure was significantly lower in eNOS- overexpressing mice than in control littermates. In the transgenic aorta, basal NO release (estimated by Nω-nitro-L-arginine-induced facilitation of the contraction by prostaglandin F(2α)) and basal cGMP levels (measured by enzyme immunoassay) were significantly increased. In contrast, relaxations of transgenic aorta in response to acetylcholine and sodium nitroprusside were significantly attenuated, and the reduced vascular reactivity was associated with reduced response of cGMP elevation to these agents as compared with control aortas. Thus, our novel mouse model of chronic eNOS overexpression demonstrates that, in addition to the essential role of eNOS in blood pressure regulation, tonic NO release by eNOS in the endothelium induces the reduced vascular reactivity to NO-mediated vasodilators, providing several insights into the pathogenesis of nitrate tolerance.
    The American Society for Clinical Investigation, Dec. 1998, Journal of Clinical Investigation, 102(12) (12), 2061 - 2071, English
    [Refereed]
    Scientific journal

■ MISC
  • 山下 智也
    <文献概要>臨床・基礎研究によって,腸内細菌叢が免疫や代謝機能を介して宿主の生体機能の維持から疾患の発症にまで関与していることが明らかになってきた.筆者らは,循環器疾患と腸内細菌叢の関連調査を実施し,臨床エビデンスのなかから新たな腸内細菌への介入方法を探索する基礎研究も進めている.Bacteroides vulgatusとBacteroides doreiの2菌種は冠動脈疾患患者で減少しており,その菌をマウスに経口投与すると動脈硬化や肥満が抑制されたため,抗炎症作用が想定できた.循環器領域では,腸内細菌代謝物としてトリメチルアミンN-オキシド(TMAO)やフェニルアセチルグルタミン(PAGln)の心血管イベント増加への関与が想定され,治療標的としても注目されている.本稿では,心不全を含む循環器疾患と腸内細菌叢ならびに腸内細菌関連代謝物との関係について,これまでの報告を紹介しながら概説したい.
    医歯薬出版(株), Nov. 2024, 医学のあゆみ, 291(5) (5), 388 - 394, Japanese

  • 【慢性炎症と心血管疾患】腸内細菌と心血管疾患
    山下 智也
    臨床・基礎研究によって腸内細菌叢が,免疫や代謝機能を介して宿主の生体機能の維持から,疾患の発症にまで関与していることが明らかになってきた。臨床医学の中では,腸内細菌叢を疾患の発症予測に利用したり,治療標的として注目され,各種疾患患者の糞便を用いた腸内細菌叢の調査が行われている。著者らは,循環器疾患と腸内細菌叢の関連調査を実施し,臨床エビデンスの中から,新たな腸内細菌への介入方法を探索する基礎研究も進めている。Bacteroides vulgatusとdoreiの2菌種は,冠動脈疾患患者で減少しており,その菌をマウスに経口投与すると動脈硬化・肥満が抑制できて,抗炎症作用が想定できた。循環器領域では,腸内細菌代謝物としてトリメチルアミンNオキシド(TMAO)が盛んに研究されており,心血管イベント増加への関与が想定され,治療標的としても注目されている。本稿では,心血管疾患と腸内細菌との関係について,主に免疫機能への影響と慢性炎症に着目して概説したい。(著者抄録)
    (株)北隆館, Nov. 2024, 別冊Bio Clinica: 慢性炎症と疾患, 13(2) (2), 54 - 59, Japanese

  • 山下 智也
    (株)メディカ出版, Oct. 2024, Nutrition Care, 17(10) (10), 952 - 957, Japanese

  • 腸内細菌と心血管疾患
    平田 健一, 江本 拓央, 山下 智也
    (一社)日本内科学会, Sep. 2024, 日本内科学会雑誌, 113(9) (9), 1525 - 1532, Japanese

  • 腸内細菌と心血管疾患
    平田 健一, 山下 智也
    (一社)日本内科学会, Feb. 2024, 日本内科学会雑誌, 113(臨増) (臨増), 82 - 85, Japanese

  • 腸内細菌と循環器疾患
    山下 智也
    (公財)ヤクルト・バイオサイエンス研究財団, Sep. 2023, 腸内フローラシンポジウム, 30, 47 - 56, Japanese

  • 山下 智也
    (一社)日本臨床化学会, Jul. 2023, 臨床化学, 52(3) (3), 170 - 178, Japanese

  • 【腸腎連関に関する最近の話題】腸血管連関とその臨床的意義
    山下 智也
    (一社)日本腎臓学会, Mar. 2023, 日本腎臓学会誌, 65(2) (2), 87 - 94, Japanese

  • 未解決の冠動脈疾患残余リスクに迫る 冠動脈疾患残余リスクとしての腸内細菌
    山下智也, 江本拓央, 平田健一
    2023, 心臓, 55(4) (4)

  • 山下 智也
    (公財)日本心臓財団, Feb. 2022, 心臓, 54(2) (2), 279 - 288, Japanese

  • 循環器疾患と腸内細菌
    山下智也
    2022, 日本臨床生理学会雑誌, 52(3) (3)

  • Microbiome and cardiovascular diseases
    山下智也, 吉田尚史, 平田健一
    2022, 臨床検査, 66(11) (11)

  • 動脈硬化に対する新しいアプローチ 急性冠症候群を引き起こすプラークのシングルセル解析
    江本拓央, 山下智也, 平田健一
    2022, 循環器専門医, 31

  • 基礎科学の進歩 腸内細菌と循環器疾患
    山下智也, 平田健一
    2022, 循環器専門医, 31

  • Role of gut microbiota in the progression of aortic aneurysm.
    山下智也, 平田健一
    2022, 循環器内科, 92(5) (5)

  • Are gut microbiota causes of cardiovascular diseases?
    山下智也, 平田健一
    2022, 医学のあゆみ, 283(14) (14)

  • Gut Microbiota and Cardiovascular Diseases
    山下智也, 山下智也, 江本拓央, 斉藤克寛, 吉田尚史, 平田健一
    2022, ICUとCCU, 46(12) (12)

  • 内科疾患治療における食と腸内細菌の重要性 循環器疾患と腸内細菌
    山下 智也, 平田 健一
    (一社)日本内科学会, Sep. 2021, 日本内科学会雑誌, 110(9) (9), 1848 - 1854, Japanese

  • 【脂質異常症の動向と治療の展望-ここまで到達した高コレステロール血症の治療】脂質異常とmicrobiome
    吉田 尚史, 山下 智也, 平田 健一
    宿主と共生する腸内細菌叢の異常が種々の疾患発症の原因となることがわかってきた。狭心症や心不全などの循環器病も例外に漏れず、それらの疾患に特徴的な腸内細菌叢が報告され、さらに腸内細菌叢がもつ多様な生体機能と循環器病との関連が解明されつつある。循環器病最大の危険因子の脂質異常症は新たな危険因子となることを示す報告が多くなされている。本稿では、腸内細菌叢について簡単に述べた後、腸内細菌叢と脂質代謝との関連研究を紹介しながら、腸内細菌に対する介入が脂質異常症への切り札となるのか、今後の展望についても述べていきたい。(著者抄録)
    (株)ライフメディコム, Sep. 2021, カレントテラピー, 39(9) (9), 844 - 846, Japanese

  • 山下 智也, 林 友鴻, 平田 健一
    <文献概要>Point 1 心臓病の病態と腸内細菌叢(マイクロバイオーム)を含む腸内環境との関係が報告されており,心腸連関が注目されている。2 腸内細菌関連代謝物であるトリメチルアミンN-オキシド(trimethylamineN-oxide:TMAO)は,心不全の予後悪化に関連する。3 腸内細菌叢のバランスを制御することで,心臓病の悪化予防ができる可能性がある。
    (株)メジカルビュー社, Jun. 2021, Heart View, 25(6) (6), 520 - 525, Japanese

  • 内科疾患治療における食と腸内細菌の重要性 循環器疾患と腸内細菌
    山下 智也, 平田 健一
    (一社)日本内科学会, Feb. 2021, 日本内科学会雑誌, 110(Suppl.) (Suppl.), 93 - 94, Japanese

  • 腸内細菌叢と循環器疾患 動脈硬化性疾患を予防する腸内常在細菌
    山下 智也
    シスメックス(株)学術本部, 2021, シスメックス学術セミナー, 43回, 55 - 65, Japanese

  • 腸内細菌叢と循環器疾患 動脈硬化性疾患を予防する腸内常在細菌
    山下 智也
    シスメックス(株)学術本部, 2021, Sysmex Journal Web, 22(1) (1), 8 - 9, Japanese


  • 【腸内細菌と疾患】腸内細菌と循環器疾患
    山下 智也, 平田 健一
    (公社)日本医師会, Dec. 2020, 日本医師会雑誌, 149(9) (9), 1583 - 1587, Japanese

  • 吉田 尚史, 山下 智也, 平田 健一
    (株)メディカルレビュー社, Dec. 2020, Pharma Medica, 38(12) (12), 57 - 60, Japanese

  • 江本 拓央, 山下 智也
    <文献概要>・動脈硬化性疾患ではBacteroides属菌が減少している.・B. vulgatus,B. doreiの2菌種の投与は糞便中のリポポリサッカライド(LPS)を低下させ,抗動脈硬化作用を発揮する.・腸内細菌由来物質であるトリメチルアミン-N-オキシド(TMAO)は動脈硬化,心不全,腎不全,血栓症に関係する.
    (株)南江堂, Sep. 2020, 内科, 126(3) (3), 434 - 437, Japanese

  • 心不全と栄養(Gut Microbiota and Their Related Metabolites in Heart Failure as Novel Therapeutic Targets)
    田畑 論子, 山下 智也, 平田 健一
    (一社)日本循環器学会, Jul. 2020, 日本循環器学会学術集会抄録集, 84回, シンポジウム19 - 4, English

  • 山下 智也, 吉田 尚史, 斎藤 克寛, 田畑 論子, 江本 拓央, 平田 健一
    (有)科学評論社, Jun. 2020, 循環器内科, 87(6) (6), 734 - 740, Japanese

  • 山下 智也
    (一社)日本糖尿病学会, Jun. 2020, 糖尿病, 63(6) (6), 382 - 385, Japanese

  • 吉田 尚史, 山下 智也, 平田 健一
    (有)科学評論社, May 2020, 循環器内科, 87(5) (5), 550 - 556, Japanese

  • 山下 智也, 吉田 尚史, 林 友鴻, 田畑 論子, 江本 拓央, 平田 健一
    (株)ライフ・サイエンス, Mar. 2020, Progress in Medicine, 40(3) (3), 223 - 229, Japanese

  • Gut microbiota and Cardiovascular diseases
    Tomoya Yamashita, Naofumi Yoshida, Tomohiro Hayashi, Tokiko Tabata, Takuo Emoto, Ken-ichi Hirata
    Lead, Mar. 2020, PROGRESS IN MEDICINE, 40(3) (3), 31 - 37, Japanese
    [Invited]
    Introduction commerce magazine

  • 血管内皮の最新トピックス 動脈硬化研究 血管内皮から腸内細菌まで
    山下 智也, 平田 健一
    日本心脈管作動物質学会, Jan. 2020, 血管, 43(1) (1), 30 - 30, Japanese

  • Tomoya Yamashita
    Lead, (株)メディカ出版, Jan. 2020, 糖尿病ケア, 17(1) (1), 31 - 33, Japanese
    Introduction commerce magazine

  • 林 友鴻, 山下 智也, 平田 健一
    <文献概要>Point ・腸には数多くの腸内細菌が生息しており,腸内細菌叢は宿主の免疫系・代謝系に大きな影響を及ぼす.・腸内細菌代謝産物であるtrimethylamine N-oxide(TMAO)の血中濃度高値は,心不全を含む循環器疾患の予後不良因子である.また,心不全患者では腸内細菌叢の変化を認めることが報告されている.・腸内細菌自体や腸内細菌代謝産物への介入が,心不全の新規治療法につながる可能性がある.
    (株)医学書院, Jan. 2020, 循環器ジャーナル, 68(1) (1), 156 - 160, Japanese
    Introduction commerce magazine

  • 吉田 尚史, 山下 智也, 平田 健一
    <文献概要>Point ・腸内細菌由来のLPSが,心不全において炎症起点となっている.・腸内細菌の機能差は,宿主のカヘキシや心筋代謝異常につながっている可能性がある.・腸上皮細胞鉱質コルチコイド受容体を介したNa吸収は,体液恒常性維持に重要な役割を果たしている.
    (株)医学書院, Jan. 2020, 循環器ジャーナル, 68(1) (1), 161 - 164, Japanese
    Introduction commerce magazine

  • 【動脈硬化診療のすべて】(VI章)動脈硬化研究のトピックス 基礎研究 腸内細菌
    山下 智也, 平田 健一
    (公社)日本医師会, Oct. 2019, 日本医師会雑誌, 148(特別2) (特別2), S326 - S328, Japanese

  • Cardiovascular diseases and gut microbiota
    山下 智也, 吉田 尚史, 江本 拓央, 林 友鴻, 田畑 論子, 平田 健一
    現在までの循環器疾患と腸内細菌に関する研究報告を、主に動脈硬化・心不全を中心に概説した。ホスファチジルコリンやカルニチンの腸内細菌関連代謝物であるトリメチルアミンNオキシドと心血管イベント発生との関連性が示され、そのバイオマーカーとしての意義や臨床での使用方法が検討課題とされている。また、心不全と腸内細菌との関係を調査した複数の臨床研究が存在するが、動脈硬化性疾患の研究と比較して、研究によって結果がかなり異なる印象があり、その意味を含めて再検討する必要があると考えられる。世界的に腸内細菌叢と疾患発症との関連性が盛んに研究されており、疾患の治療や予防の標的としても注目されるようになっている。
    Lead, (一財)医薬品医療機器レギュラトリーサイエンス財団, Sep. 2019, 医薬品医療機器レギュラトリーサイエンス, 50(9) (9), 504 - 512, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌と疾患】 循環器疾患・コレステロール代謝と腸内細菌
    山下智也, Hirata Ken-ichi
    (一社)日本心臓病学会, Sep. 2019, BIO Clinica, 67回(14号) (14号), T3 - T3, Japanese
    [Invited]
    Introduction commerce magazine

  • 山下 智也, 平田 健一
    Lead, (一社)日本循環器学会, Aug. 2019, 循環器専門医, 28, 81 - 84, Japanese
    Introduction scientific journal

  • Atherosclerosis and gut microbiota
    田畑論子, 山下智也, 平田健一
    Apr. 2019, カレントテラピー, 37(4) (4), 388 - 394, Japanese
    Introduction commerce magazine

  • Gut microbiota ans atherosclerosis
    山下智也, 平田健一
    Lead, Mar. 2019, Modern Media, 65(3) (3), 49 - 53, Japanese
    Introduction commerce magazine

  • Atherosclerosis and gut microbiota
    Naofumi Yoshia, Tomoya Yamashita, Ken-ichi Hirata
    Feb. 2019, Cardiac Practice, 29(4) (4), 29 - 32, Japanese
    Introduction commerce magazine

  • 【動脈硬化UPDATE】 基礎 腸内細菌と動脈硬化性疾患 現在までのエビデンスと今後の展望
    吉田尚史, 山下智也, Hirata Ken-ichi
    ヒトは血管とともに老いる、といわれるように、動脈硬化性疾患はわが国において死因の第2位を占める。動脈硬化性疾患は自然免疫と獲得免疫の両者が関与している慢性炎症性疾患のひとつであり、抗体医薬を用いた治療がすでに実臨床に登場している。しかし、心筋梗塞や脳梗塞の発症は急性であり、おおよそ慢性炎症という言葉からはかけ離れたもので、発症を予知することは困難である。さらに高血圧、糖尿病、脂質異常症、肥満、喫煙などの動脈硬化性疾患発症の危険因子に対する適切な介入後も動脈硬化のリスクは残存しており、それら残余リスクの解明と動脈硬化に対する新規予防法・治療法の開発はわれわれ循環器内科医の使命である。近年の研究により、腸内細菌は生体恒常性維持のマスター臓器と考えられており、本稿では、腸内細菌と動脈硬化性疾患について著者らの研究成果も交えながら概説し、腸内細菌に対する介入が、増加する動脈硬化性疾患への切り札となるのか、考察していきたい。(著者抄録)
    医歯薬出版(株), Feb. 2019, 医学のあゆみ, 268(5) (5), 343 - 348, Japanese
    [Invited]
    Introduction commerce magazine

  • 【心不全(第2版)上-最新の基礎・臨床研究の進歩-】 心不全の基礎研究 心不全の分子機序 多臓器連関の基礎研究 腸内細菌と心不全
    山下智也, 林友鴻, Hirata Ken-ichi
    Dec. 2018, 日本臨床, 76(増刊9 心不全(上)) (増刊9 心不全(上)), 358 - 362, Japanese
    [Invited]
    Introduction commerce magazine

  • 腸管免疫・腸内細菌叢と冠動脈疾患
    Yamashita Tomoya, 吉田尚史, 林友鴻, 江本拓央, 溝口泰司, 笠原和之, 佐々木直人, Hirata Ken-ichi
    (有)科学評論社, Nov. 2018, 循環器内科, 84(5) (5), 584 - 590, Japanese
    [Invited]
    Introduction commerce magazine

  • 【動脈硬化の早期診断法と予防対策-健康寿命延伸をめざして】 腸内細菌と動脈硬化
    吉田尚史, Yamashita Tomoya, Hirata Ken-ichi
    (株)ライフメディコム, Nov. 2018, カレントテラピー, 36(11) (11), 1116 - 1121, Japanese
    [Invited]
    Introduction commerce magazine

  • 【脂質代謝と心臓血管病:up-to-date】 脂質代謝と心臓血管病における腸内細菌の役割
    Yamashita Tomoya, Hirata Ken-ichi
    Oct. 2018, The Lipid, 29(4号) (4号), 384 - 391, Japanese
    [Invited]
    Introduction commerce magazine

  • 腸内細菌と循環器疾患
    Hirata Ken-ichi, Yamashita Tomoya
    Sep. 2018, 日本内科学会雑誌, 107(9号) (9号), 1906 - 1912, Japanese
    [Refereed]
    Introduction scientific journal

  • Bicuspid Aortic Valve-Associated Aortic Dilatation - What Is the Mechanism of Bicuspid Aortopathy
    Yamashita Tomoya, Hayashi T, Tabata T, Hirata Ken-ichi
    Sep. 2018, Circ J, 82(10) (10), 2470 - 2471, English
    [Refereed]
    Introduction scientific journal

  • 病態連関の新知見 腸内細菌と動脈硬化
    Yamashita Tomoya, Hirata Ken-ichi
    Aug. 2018, 循環plus, 18(6号) (6号), 10 - 12, Japanese
    Introduction commerce magazine

  • 心不全の革新的予防戦略 心不全患者における腸内フローラおよび腸内細菌由来代謝産物の変化
    林友鴻, Yamashita Tomoya, Hirata Ken-ichi
    Aug. 2018, 循環器専門医, 27, 3 - 8, Japanese
    Introduction scientific journal

  • 心房細動・心不全と腸内細菌
    林友鴻, Yamashita Tomoya, Hirata Ken-ichi
    Jul. 2018, 循環器内科, 84(1号) (1号), 86 - 92, Japanese
    Introduction scientific journal

  • Naofumi Yoshida, Tomoya Yamashita, Ken-Ichi Hirata
    Recent evidence has suggested that the gut microbiome is involved in human health and diseases, such as inflammatory bowel disease, liver cirrhosis, rheumatoid arthritis, and type 2 diabetes. Cardiovascular diseases, which are associated with high morbidity and mortality across the world, are no exception. Increasing evidence has suggested a strong relationship between the gut microbiome and the progression of cardiovascular diseases. We first reported such a relationship with coronary artery disease two years ago. Next-generation sequencing techniques, together with bioinformatics technology, constantly and dramatically expand our knowledge of the complex human gut bacterial ecosystem and reveal the exact role of this bacterial ecosystem in cardiovascular diseases via the functional analysis of the gut microbiome. Such knowledge may pave the way for the development of further diagnostics and therapeutics for prevention and management of cardiovascular diseases. The aim of the current review is to highlight the relationship between the gut microbiome and their metabolites, and the development of cardiovascular diseases by fostering an understanding of recent studies.
    29 Jun. 2018, Diseases (Basel, Switzerland), 6(3) (3), English, International magazine
    [Refereed]

  • 動脈硬化性疾患とがんにおける免疫チェックポイントタンパク質と制御性T細胞の役割
    佐々木直人, 佐々木直人, 山下智也, 平田健一, 力武良行
    25 Jun. 2018, 日本動脈硬化学会総会・学術集会プログラム・抄録集(Web), 50th, 186 (WEB ONLY), Japanese

  • 紫外線B波照射はCD4陽性Foxp3陽性制御性T細胞を増幅し,アンギオテンシンII誘導性マウス大動脈瘤の形成を抑制する
    林友鴻, 佐々木直人, 山下智也, 溝口泰司, 江本拓央, AMIN Hilman Zulkifli, 淀井(眞弓)景子, 松本卓也, 笠原和之, 吉田尚史, 田畑論子, 北野尚樹, 福永淳, 錦織千佳子, 力武良行, 平田健一
    (一社)日本動脈硬化学会, Jun. 2018, 日本動脈硬化学会総会・学術集会プログラム・抄録集(Web), 50回, 262 - 262, Japanese

  • Tomoya Yamashita, Tomohiro Hayashi, Naofumi Yoshida, Ken-Ichi Hirata
    25 May 2018, Circulation journal : official journal of the Japanese Circulation Society, 82(6) (6), 1507 - 1509, English, Domestic magazine
    [Refereed]
    Introduction scientific journal

  • 【腸とアンチエイジング】 動脈硬化と腸内環境
    溝口泰司, Yamashita Tomoya, Hirata Ken-ichi
    Feb. 2018, アンチ・エイジング医学, 14(1号) (1号), 045 - 050, Japanese
    [Invited]
    Introduction scientific journal

  • 【マイクロバイオームと生体恒常性・疾患】 循環器疾患とマイクロバイオーム
    Yamashita Tomoya, Hirata Ken-ichi
    Feb. 2018, 化学療法の領域, 34(3号) (3号), 433 - 440, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌と臨床医学】 循環器疾患と腸内細菌
    山下智也, Hirata Ken-ichi
    Jan. 2018, 医学のあゆみ, 264(1号) (1号), 88 - 93, Japanese
    [Invited]
    Introduction commerce magazine

  • 紫外線照射による動脈硬化性疾患に対する抑制効果
    佐々木直人, 佐々木直人, 溝口泰司, 溝口泰司, AMIN Hilman Zulkifli, AMIN Hilman Zulkifli, 堀部紗世, 河内正二, 山下智也, 平田健一, 力武良行, 力武良行
    2018, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27M‐pm18, Japanese

  • 糖尿病をめぐる診療科リレー 循環器内科 循環器診療の中での糖尿病・耐糖能異常の意義
    山下智也, 新家俊郎, Hirata Ken-ichi
    Nov. 2017, DM Ensemble, 6(3号) (3号), 40 - 44, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内フローラと神経・精神疾患】 腸内フローラと全身疾患 動脈硬化
    山下智也, Hirata Ken-ichi
    Nov. 2017, Clinical Neuroscience, 35(11号) (11号), 1312 - 1315, Japanese
    [Invited]
    Introduction commerce magazine

  • 山下智也, Hirata Ken-ichi
    近年、疾患発症と腸内細菌叢との関連が調査され、代謝疾患・免疫疾患・悪性腫瘍などの分野の報告が相次いでいる。心血管病の分野では、腸内細菌由来代謝物のトリメチルアミンNオキシド(TMAO)が動脈硬化を悪化させ、心血管イベントの増加に関連すると報告され、循環器疾患の治療標的として注目されている。本稿では、動脈硬化をはじめ高血圧や心不全といった心血管病の病態と腸内細菌との関連について、世界的な研究の動向と我々のグループからの報告を紹介して、今後の展望を述べたい。
    公益社団法人 日本薬学会, Nov. 2017, ファルマシア, 53(11) (11), 1073 - 1076, Japanese
    [Invited]
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  • 【いま知りたい!腸内フローラのABC】 腸内フローラと疾患のかかわり 循環器疾患
    山下智也, Hirata Ken-ichi
    Oct. 2017, Medical Technology, 45(10号) (10号), 1038 - 1042, Japanese
    [Invited]
    Introduction commerce magazine

  • 【動脈硬化症 基礎から臨床へ】 腸から動脈硬化を予防する 腸内細菌叢と動脈硬化性疾患との関わり
    Yamashita Tomoya
    Oct. 2017, 日本医科大学医学会雑誌, 13(4号) (4号), 205 - 209, Japanese
    [Invited]
    Introduction scientific journal

  • Atsushi Suzuki, Koji Fukuzawa, Tomoya Yamashita, Naoto Sasaki, Ken-ichi Hirata
    OXFORD UNIV PRESS, Aug. 2017, EUROPACE, 19(8) (8), 1409 - 1410, English
    Report scientific journal

  • 【動脈硬化の新しいバイオマーカー】 動脈硬化性疾患の新規バイオマーカーとしての腸内細菌叢
    山下智也, Hirata Ken-ichi
    Aug. 2017, 医療と検査機器・試薬, 40(4号) (4号), 277 - 282, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内フローラ研究の最前線】 動脈硬化と腸内フローラ
    溝口泰司, 山下智也, Hirata Ken-ichi
    Aug. 2017, The GI Forefront, 13(1号) (1号), 29 - 32, Japanese
    [Invited]
    Introduction commerce magazine

  • Gut microbiota regulate both cholesterol metabolism and chronic inflammation in ApoE-deficient mice
    笠原和之, 山下智也, Hirata Ken-ichi
    科学評論社, Jul. 2017, 内分泌・糖尿病・代謝内科, 45(1) (1), 68 - 73, Japanese
    [Invited]
    Introduction commerce magazine

  • 【動脈・静脈の疾患(下)-最新の診断・治療動向-】 腸内細菌叢と心血管病
    山下智也, Hirata Ken-ichi
    Jul. 2017, 日本臨床, 75(増刊5 動脈・静脈の疾患(下)) (増刊5 動脈・静脈の疾患(下)), 1101 - 1106, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌-糖尿病・肥満にまつわる10 topics】 (トピック7)動脈硬化と腸内細菌
    山下智也, Hirata Ken-ichi
    Jun. 2017, 糖尿病診療マスター, 15(6号) (6号), 504 - 509, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌と生活習慣病】 腸内細菌と循環器疾患
    吉田尚史, 山下智也, Hirata Ken-ichi
    (株)医学出版, May 2017, 月刊糖尿病, 9(5) (5), 34 - 42, Japanese
    [Invited]
    Introduction commerce magazine

  • 【呼吸器疾患とマイクロバイオーム】 基礎医学とのダイアローグ 腸内細菌と動脈硬化
    江本拓央, 山下智也, Hirata Ken-ichi
    May 2017, THE LUNG-perspectives, 25(2号) (2号), 184 - 188, Japanese
    [Invited]
    Introduction commerce magazine

  • 【消化管と糖尿病】 腸内細菌と動脈硬化
    溝口泰司, 山下智也, Hirata Ken-ichi
    Apr. 2017, Diabetes Frontier, 28(2号) (2号), 158 - 162, Japanese
    [Invited]
    Introduction commerce magazine

  • 危険因子 腸内細菌叢(腸内フローラ)
    江本拓央, 山下智也, Hirata Ken-ichi
    Mar. 2017, 動脈硬化予防, 16(1号) (1号), 90 - 93, Japanese
    Introduction commerce magazine

  • Tomoya Yamashita
    Atherosclerosis is a chronic inflammatory disease. Interventions targeting the inflammatory process could provide new strategies for preventing atherosclerotic cardiovascular diseases (CVD). Previously, we have reported that oral administration of anti-CD3 antibodies, or active vitamin D3, reduced atherosclerosis in mice via recruiting regulatory T cells and tolerogenic dendritic cells to the gut-associated lymphoid tissues. From this, it is reasonable to propose that the intestine could be a novel therapeutic target for prevention of atherosclerotic CVD. Recently, the association between cardio-metabolic diseases and gut microbiota has attracted increased attention. Gut microbiota, reported to be highly associated with intestinal immunity and metabolism, were shown to aggravate CVD by contributing to the production of trimethylamine-N-oxide (TMAO), a pro-atherogenic compound. We have also previously investigated the relationship between patient susceptibility to coronary artery disease (CAD) and gut microbiota. We found that the order Lactobacillales was significantly increased and the phylum Bacteroidetes was decreased in CAD patients compared with control patients. In this review article, we discuss the evidence for the relationship between the gut microbiota and cardio-metabolic diseases, and consider the gut microbiota as new potential diagnostic and therapeutic tool for treating CVD.
    JAPAN ATHEROSCLEROSIS SOC, 2017, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 24(2) (2), 110 - 119, English
    [Refereed]
    Book review

  • 【虚血性心疾患UPDATE】 冠動脈疾患基礎研究の進歩 腸管免疫、腸内細菌と冠動脈硬化
    山下智也, Hirata Ken-ichi
    Nov. 2016, 医学のあゆみ, 259(6号) (6号), 597 - 603, Japanese
    [Invited]
    Introduction commerce magazine

  • 腸内細菌と諸疾患-ここまで明らかになった腸内細菌と全身疾患の関連】 循環器疾患と腸内細菌
    江本拓央, Yamashita Tomoya, Hirata Ken-ichi
    Nov. 2016, カレントテラピー, 34(11) (11), 1089 - 1094, Japanese
    Introduction commerce magazine

  • 注目される用語の解説 制御性T細胞
    Sasaki Naoto, 山下智也, Hirata Ken-ichi
    Sep. 2016, 動脈硬化予防, 15(3号) (3号), 89 - 91, Japanese
    [Invited]
    Introduction commerce magazine

  • 腸内細菌と疾患 腸内細菌と循環器疾患
    Yamashita Tomoya, Hirata Ken-ichi, 山下智也, 平田健一山下智也, 平田健一山下智也, 平田健一
    Sep. 2016, 日本内科学会雑誌, 105(9号) (9号), 1706 - 1711, Japanese
    [Invited]
    Introduction scientific journal

  • Gut Microbiota and Cardiovascular Diseases
    Yamashita Tomoya, Hirata Ken-ichi
    最新医学社, Sep. 2016, 最新医学, 71(9) (9), 1795 - 1801, Japanese
    [Invited]
    Introduction commerce magazine

  • 【最新冠動脈疾患学(上)-冠動脈疾患の最新治療戦略-】 冠動脈疾患の発症・進展に関わる危険因子 冠動脈疾患の基礎疾患と環境因子
    Yamashita Tomoya, 江本拓央, Hirata Ken-ichi
    Jun. 2016, 最新冠動脈疾患学(上), 74(4) (4), 211 - 2106, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌叢からみた臨床の最前線-ベールを脱いだ体内パートナーの機能】 腸内細菌と動脈硬化
    Yamashita Tomoya, Hirata Ken-ichi
    診断と治療社, Feb. 2016, 診断と治療, 104(2) (2), 171 - 174, Japanese
    [Invited]
    Introduction commerce magazine

  • 【腸内細菌と脂質】 腸内細菌から連鎖する病態の理解 腸内細菌と動脈硬化
    Yamashita Tomoya, Hirata Ken-ichi
    2016, The Lipid, 27(2) (2), 159 - 164, Japanese
    [Invited]
    Introduction commerce magazine

  • 【最近の日本人の肥満症-新知見が拓くこれからの肥満症診療】 肥満症のメカニズム 腸内細菌叢と肥満
    Yamashita Tomoya, Hirata Ken-ichi
    Jan. 2016, カレントテラピー, 34(1号) (1号), 33 - 38, Japanese
    Introduction commerce magazine

  • Tomoya Yamashita, Takuo Emoto, Naoto Sasaki, Ken-Ichi Hirata
    Gut microbiota have been attracting increased attention in many fields of medicine recently. We can perform a comprehensive analysis of gut microbiota using next-generation sequencing techniques together with bioinformatics technology, which expands our knowledge of a large ecosystem consisting of a host and gut microbiota. We summarize some reports about the correlations between gut microbiota and metabolic disorders, particularly atherosclerosis, and discuss future directions for the diagnostic or therapeutic potential of gut microbiota. To take simple examples, we demonstrated that the order Lactobacillales was significantly increased while the phylum Bacteroidetes was significantly decreased in coronary artery disease (CAD) patients compared with controls or healthy volunteers. The characteristics of gut microbiota in type 2 diabetes and dyslipidemia have been reported. However, these studies have limitations, and the biological significance of gut microbiota and the causal relationships are still controversial. We hope the reports listed in this review article might lead to the development of a novel therapy to prevent CAD via modulating gut microbiota or their metabolites.
    International Heart Journal Association, 2016, International Heart Journal, 57(6) (6), 663 - 671, English
    [Refereed]
    Book review

  • 【腸内細菌は病気とどう関連するか】 腸内細菌と動脈硬化
    山下智也, Hirata Ken-ichi
    東京医学社, Dec. 2015, 成人病と生活習慣病, 45(12) (12), 1523 - 1529, Japanese
    Introduction commerce magazine

  • Gut Microbiota and Atherosclerosis
    江本拓央, Yamashita Tomoya, Hirata Ken-ichi
    医学書院, Dec. 2015, 呼吸と循環, 63(12) (12), 1209 - 1215, Japanese
    Introduction commerce magazine

  • 【腸内細菌up to date:今まさに明らかになりつつある全身疾患への影響】 腸内細菌と循環器疾患
    笠原和之, Yamashita Tomoya, Hirata Ken-ichi
    Oct. 2015, Pharma Medica, 33(10号) (10号), 23 - 26, Japanese
    Introduction commerce magazine

  • 【腸内フローラが見せる新たな世界と疾患メカニズム】 腸内細菌と動脈硬化
    Yamashita Tomoya, Hirata Ken-ichi
    Oct. 2015, 血管医学, 16(3号) (3号), 237 - 242, Japanese
    Introduction commerce magazine

  • 【ヒトマイクロバイオーム研究UPDATE】 腸内細菌と循環器疾患
    江本拓央, Yamashita Tomoya, Hirata Ken-ichi
    Oct. 2015, 臨床化学, 44(4号) (4号), 282 - 289, Japanese
    Introduction commerce magazine

  • Tomoya Yamashita, Kazuyuki Kasahara, Takuo Emoto, Takuya Matsumoto, Taiji Mizoguchi, Naoki Kitano, Naoto Sasaki, Ken-ichi Hirata
    Atherosclerosis is considered a chronic inflammatory disease and an intervention targeting the inflammatory process could be a new therapeutic strategy for preventing atherosclerotic cardiovascular diseases (CVD). We hypothesized that the intestine, which is considered the biggest immune organ in the human body, could be a therapeutic target for preventing CVD. We demonstrated that oral administration of anti-CD3 antibody or an active form of vitamin D-3 reduced atherosclerosis in mice via induction of regulatory T cells and tolerogenic dendritic cells in the gut-associated lymphoid tissues. Similar to regulatory immune responses achieved by oral tolerance, our method had systemic effects that ultimately contributed towards atherosclerosis reduction. Recently, we have been interested in the gut microbiota, which have been reported as highly associated with intestinal immunity and systemic metabolic disorders, including obesity and diabetes. Notably, the guts of obese individuals are predominantly colonized by Firmicutes over Bacteroidetes. The association between atherosclerosis and microbiota has been attracting increased attention, and gut microbiota have been shown to participate in the metabolism of a proatherogenic compound called trimethylamine-N-oxide (TMAO) and aggravate CVD. Our investigation of the relationship between susceptibility to CVD and the gut microbiota revealed a characteristic flora type. Here, we discuss the evidence for the relationship between the gut microbiota and cardiometabolic diseases, and consider the gut microbiota as new potential therapeutic targets for treating CVD.
    JAPANESE CIRCULATION SOC, Sep. 2015, CIRCULATION JOURNAL, 79(9) (9), 1882 - 1890, English
    Book review

  • 動脈硬化研究の新展開 未知の治療ターゲットを求めて 心血管病の治療標的としての腸管免疫と腸内細菌
    Yamashita Tomoya, 佐々木直人, Hirata Ken-ichi
    Sep. 2015, 循環器専門医, 23(2号) (2号), 189 - 195, Japanese
    Introduction scientific journal

  • 【血管内皮細胞関連因子】 一酸化窒素(NO)
    Yamashita Tomoya
    先端医学社, Sep. 2015, Thrombosis Medicine, 5(3) (3), 221 - 226, Japanese
    [Invited]
    Introduction commerce magazine

  • Therapeutic Modulation of Intestinal Immunity and Gut Microbiota in Cardiovascular Diseases
    笠原和之, Yamashita Tomoya, Hirata Ken-ichi
    医学書院, Sep. 2015, 呼吸と循環, 63(9) (9), 840 - 846, Japanese
    Introduction commerce magazine

  • Tomoya Yamashita, Naoto Sasaki, Kazuyuki Kasahara, Ken-ichi Hirata
    Atherosclerosis is believed to be a chronic inflammation of the arterial wall and various immune cells of innate and adaptive immunity involves in the pathogenesis of atherosclerosis. Based on this notion, several anti-inflammatory strategies for prevention of atherosclerosis have been examined mainly using animal models. Vaccination or mucosal immunization with athero-antigens comes under candidate therapeutic methods for antigen-specific prevention of atherosclerosis. Immune suppression mediated by regulatory T cells (Tregs) could be another method to regulate pathogenic chronic inflammation in atherogenesis. Inducible Tregs are reported to differentiate peripherally in the intestine and we have been interested in the oral tolerance, in which not only Tregs but also tolerogenic dendritic cells play crucial roles. We demonstrated that modulation of the intestinal immunity including oral tolerance could be a novel therapy against atherosclerosis. Further, downregulation of effector T cell response and/or Treg predominant condition was shown to induce atherosclerosis regression and inhibit the progression of aneurysm.In clinical situations, none of the approaches to specifically and directly treat inflammation to prevent cardiovascular events or reduce atherosclerosis in human individuals were successful, although high-sensitive C-reactive protein is shown to have a strong relationship with recurrent events of cardiovascular diseases in several randomized clinical trials. Now two randomized placebo-controlled clinical trials evaluating anti-inflammatory agents are being conducted in the USA and Canada to clarify whether targeting the inflammation itself will reduce cardiovascular events and risks.In this review, we present the current understanding of anti-inflammatory and immune-modulation therapies against atherosclerosis and discuss the future perspectives.
    Japanese College of Cardiology (Nippon-Sinzobyo-Gakkai), 01 Jul. 2015, Journal of Cardiology, 66(1) (1), 1 - 8, English
    Book review

  • 【慢性炎症制御による加齢関連疾患治療の展望】 慢性炎症制御による動脈硬化予防
    Yamashita Tomoya, 佐々木直人, Hirata Ken-ichi
    Jun. 2015, 別冊Bio Clinica: 慢性炎症と疾患, 4(2号) (2号), 50 - 55, Japanese
    Introduction commerce magazine

  • 【動脈硬化予防の新たなバイオマーカー】 腸内細菌叢
    Yamashita Tomoya, Hirata Ken-ichi
    Apr. 2015, 動脈硬化予防, 14(1号) (1号), 58 - 64, Japanese
    Introduction commerce magazine

  • Atsushi Suzuki, Koji Fukuzawa, Tomoya Yamashita, Akihiro Yoshida, Naoto Sasaki, Takuo Emoto, Asumi Takei, Ryudo Fujiwara, Tomoyuki Nakanishi, Soichiro Yamashita, Akinori Matsumoto, Hiroki Konishi, Hirotoshi Ichibori, Nobutaka Inoue, Ken-ichi Hirata
    ELSEVIER SCIENCE INC, Mar. 2015, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 65(10) (10), A466 - A466, English
    Summary international conference

  • Regulatory T Cells and Tolerogenic Dendritic Cells as Critical Immune Modulators in Atherogenesis
    Naoto Sasaki, Tomoya Yamashita, Kazuyuki Kasahara, Masafumi Takeda, Ken-ichi Hirata
    Innate and adaptive immunity has been shown to be critically involved in the pathogenesis of atherosclerosis. In particular, immune suppression mediated by regulatory T cells (Tregs) or tolerogenic dendritic cells (DCs) serves as a vital mechanism for regulating pathogenic chronic inflammation in atherogensis, suggesting that promotion of endogenous regulatory immune responses could be a possible therapeutic approach to suppress atherosclerotic disease. In this review, we discuss the possible role of Tregs and tolerogenic DCs in the prevention of atherosclerosis and the promising strategies to prevent or cure atherosclerotic disease by modulating regulatory immune responses mediated by these suppressor cells.
    BENTHAM SCIENCE PUBL LTD, 2015, CURRENT PHARMACEUTICAL DESIGN, 21(9) (9), 1107 - 1117, English
    Book review

  • 腸内細菌と動脈硬化 動脈硬化性疾患を腸内細菌叢への介入により治療できるのか?
    Yamashita Tomoya
    Dec. 2014, メディカル朝日, 43(12号) (12号), 34 - 35, Japanese
    [Invited]
    Introduction commerce magazine

  • Regulation of metabolic syndrome by short chain fatty acids
    江本 拓央, Yamashita Tomoya, Hirata Ken-ichi
    科学評論社, Nov. 2014, 内分泌・糖尿病・代謝内科, 39(5) (5), 415 - 421, Japanese
    Introduction commerce magazine

  • 【腸内細菌と疾患】 腸内細菌と循環器疾患 腸から動脈硬化は予防できるのか
    Yamashita Tomoya, 笠原 和之, 佐々木 直人, Hirata Ken-ichi
    Oct. 2014, 医学のあゆみ, 251(1号) (1号), 100 - 106, Japanese
    Introduction commerce magazine

  • 腸内細菌と代謝障害 腸内細菌と動脈硬化
    Yamashita Tomoya
    Sep. 2014, Therapeutic Research, 35(9号) (9号), 789 - 791, Japanese
    [Invited]
    Introduction commerce magazine

  • 腎神経アブレーション再考 新展開はあるか? 腸内フローラへの介入と腸管免疫修飾による動脈硬化予防
    山下 智也, Hirata Ken-ichi
    Jul. 2014, 日本循環制御医学会総会プログラム・抄録集 35回, 41, Japanese
    Meeting report

  • 【腸の世界-腸内フローラ(細菌叢)と健康・疾病】 (Part 3)腸内フローラと疾病 腸内細菌と動脈硬化 腸内細菌は新たな心血管病の治療標的となり得るか
    笠原 和之, Yamashita Tomoya, 佐々木 直人, Hirata Ken-ichi
    エヌ・ティー・エス, Jul. 2014, 遺伝: 生物の科学, 68(4) (4), 358 - 362, Japanese
    Introduction commerce magazine

  • Gut microbiota and cardiovascular disease
    Yamashita Tomoya, 笠原 和之, 佐々木 直人, Hirata Ken-ichi
    科学評論社, Jun. 2014, 循環器内科, 75(6) (6), 610 - 617, Japanese
    Introduction commerce magazine

  • 腸から動脈硬化を予防する
    山下 智也, Hirata Ken-ichi
    May 2014, 日本老年医学会雑誌, 51(Suppl.) (Suppl.), 33, Japanese
    Meeting report

  • 【臓器代謝ネットワーク:分子機構とその破綻による病態から臨床的意義まで】 腸血管連関とその臨床的意義
    Yamashita Tomoya, Hirata Ken-ichi
    学研メディカル秀潤社 ; 1982-, Apr. 2014, 細胞工学, 33(5) (5), 486 - 488, Japanese
    Introduction commerce magazine

  • Gut microbiota and atherosclerosis
    Yamashita Tomoya, Hirata Ken-ichi
    日本肥満学会, Apr. 2014, 肥満研究, 20(1) (1), 7 - 12, Japanese
    Introduction scientific journal

  • 【プラークバイオロジーの解明から新しい冠動脈イメージングまで】 プラーク形成・破裂と制御性T細胞
    笠原 和之, Yamashita Tomoya, 佐々木 直人, Hirata Ken-ichi
    Apr. 2014, The Lipid, 25(2号) (2号), 122 - 128, Japanese
    Introduction commerce magazine

  • 【腸内フローラと健康・疾病とのかかわり】 腸内フローラと疾病とのかかわり 動脈硬化
    Yamashita Tomoya, 笠原 和之, 佐々木 直人, Hirata Ken-ichi
    Mar. 2014, 臨床と微生物, 41(2号) (2号), 157 - 163, Japanese
    Introduction commerce magazine

  • 【常在細菌叢が操るヒトの健康と疾患】 (第3章)疾患における常在細菌叢のふるまいと治療的介入 代謝関連疾患 動脈硬化と腸内細菌 腸から動脈硬化性疾患は予防できるのか?
    Yamashita Tomoya, 笠原 和之, 佐々木 直人, Hirata Ken-ichi
    Mar. 2014, 実験医学, 32(5号) (5号), 773 - 779, Japanese
    [Invited]
    Introduction commerce magazine

  • 高心拍出性ショックを伴う肺高血圧症を呈し急性期診断に苦慮した一例
    清水真央, 中山和彦, 絹谷洋人, 新倉悠人, 笠松朗, 高谷具史, 新家俊郎, 山下智也, 伊阪大二, 江本憲昭, 平田健一
    2014, 日本循環器学会近畿地方会(Web), 118th

  • 動脈硬化の最新知見 免疫制御による動脈硬化性疾患予防・治療戦略
    佐々木 直人, 山下 智也, Hirata Ken-ichi
    Jan. 2014, 血管, 37(1号) (1号), 20, Japanese
    Meeting report

  • YAMASHITA Tomoya, KASAHARA Kazuyuki, SASAKI Naoto, HIRATA Ken-ichi
    The gut is an organ that absorbs nutrition and water, and it also plays a critical role as an immunoregulatory organ. Recent basic and clinical research studies have reported the relationships among the gut microbiota, intestinal immunoregulatory, and the incidence of several diseases. Especially, recent papers have reported the significance of gut bacterial flora in the pathogenesis of obesity and metabolic diseases including diabetes mellitus. Similarly, several papers have reported the significance of gut microbiota and the intestinal immune system in atherogenesis. In this article, we introduce and summarize the state of the art of this research area and discuss future perspectives.
    JAPAN BIFIDUS FOUNDATION, Jan. 2014, BIFIDUS--Flores,Fructus et Semina, 28(1) (1), 1 - 5, Japanese
    [Invited]
    Introduction scientific journal

  • 抗CD3抗体とIL-2複合体の併用療法は、アポE欠損マウスにおけるエフェクターT細胞と制御性T細胞のバランスを変化させ、動脈硬化を抑制する
    笠原 和之, 佐々木 直人, 山下 智也, 佐々木 義浩, 淀井 景子, 江本 拓央, 松本 卓也, Hirata Ken-ichi
    Jan. 2014, 血管, 37(1号) (1号), 36, Japanese
    Meeting report

  • アンジオテンシンII負荷腹部大動脈瘤マウスモデルにおける制御性T細胞の役割の検討
    淀井 景子, 山下 智也, 佐々木 直人, 北 智之, 笠原 和之, 佐々木 義浩, 松本 卓也, 江本 拓央, 溝口 泰司, Hirata Ken-ichi
    Jan. 2014, 血管, 37(1号) (1号), 36, Japanese
    Meeting report

  • Activation of Skin Dendritic Cells Controls Atherogensis in Mice
    Naoto Sasaki, Tomoya Yamashita, Kazuyuki Kasahara, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Ken-ichi Hirata
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2013, CIRCULATION, 128(22) (22), English
    Summary international conference

  • A Novel Combination Therapy with Anti-CD3 Antibody and IL-2 Complexes Against Atherosclerosis Targeting Effector T Cells and Regulatory T Cells
    Kazuyuki Kasahara, Tomoya Yamashita, Naoto Sasaki, Yoshihiro Sasaki, Keiko Yodoi, Ken-ichi Hirata
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2013, CIRCULATION, 128(22) (22), English
    Summary international conference

  • 心臓と他臓器のコミュニケーションを探る 臓器関連から考える新しい循環器病治療戦略 腸管は心血管病予防の新たな治療ターゲットになる
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    社団法人日本循環器学会, 25 Sep. 2013, 循環器専門医, 21(2) (2), 291 - 296, Japanese
    Introduction scientific journal

  • 【脂質異常症-基礎・臨床研究の最新知見-】 活性型ビタミンD3の抗動脈硬化作用
    Yamashita Tomoya, Hirata Ken-ichi
    Jun. 2013, 日本臨床, 71(増刊3 脂質異常症) (増刊3 脂質異常症), 689 - 692, Japanese
    [Invited]
    Introduction commerce magazine

  • 循環器内科学 腸管免疫修飾による動脈硬化予防
    Yamashita Tomoya, 平田 健一
    Apr. 2013, 医学のあゆみ, 245(2号) (2号), 189 - 190, Japanese
    [Invited]
    Introduction scientific journal

  • 原因不明疾患とNormal Microbiota 腸内フローラへの介入と腸管免疫修飾による動脈硬化予防
    Yamashita Tomoya, 佐々木 直人, 平田 健一
    Apr. 2013, 腸内細菌学雑誌, 27(2号) (2号), 93 - 94, Japanese
    [Invited]
    Introduction scientific journal

  • 内分泌 臨床分野での進歩 腸内環境と動脈硬化
    Yamashita Tomoya, Hirata Kenichi
    中外医学社, Jan. 2013, Annual Review糖尿病・代謝・内分泌, 2013, 211 - 216, Japanese
    [Refereed][Invited]
    Introduction scientific journal

  • Activation of Regulatory T Cells by Ultraviolet Irradiation Controls Atherogenesis in Mice
    Naoto Sasaki, Tomoya Yamashita, Kazuyuki Kasahara, Kenji Nakajima, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Masafumi Takeda, Ken-ichi Hirata
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2012, CIRCULATION, 126(21) (21), English
    Summary international conference

  • メタボリックシンドローム最新情報 腸管免疫と慢性炎症 腸管免疫修飾による新規動脈硬化予防法の開発
    Yamashita Tomoya, Sasaki Naoto, Hirata Kenichi
    Jul. 2012, 日本動脈硬化学会総会プログラム・抄録集, (44回) (44回), 166, Japanese
    Meeting report

  • Regulatory T Cells in Atherogenesis
    Naoto Sasaki, Tomoya Yamashita, Masafumi Takeda, Ken-ichi Hirata
    Atherosclerosis is believed to be an inflammatory condition of the arterial wall. It has become apparent that various types of cells of innate and adaptive immunity participate in atherogenesis. T cells are of particular interest because they mediate pathogenic immune responses involved in the acceleration of atherosclerosis. Recent studies from several independent groups indicated that subsets of regulatory T cells (Tregs) actively mediate immunologic tolerance and inhibit atherosclerosis development or progression through the down-regulation of effector T-cell responses. It is likely that there is an imbalance between pathogenic effector T cells and Tregs under atherosclerotic conditions. Recent evidence suggests that in addition to the thymus, gut-associated lymphoid tissues are the main sites for the generation of several subsets of peripherally inducible Tregs. This indicates that intervention in the gut environment to promote an endogenous regulatory immune response may serve as a possible therapeutic approach to suppress atherosclerotic diseases. In this review, we discuss not only the possible role of Tregs in the prevention of atherosclerosis, but also promising strategies to prevent or cure atherosclerotic diseases by promoting an endogenous regulatory immune response, particularly by oral immune modulation.
    JAPAN ATHEROSCLEROSIS SOC, 2012, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(6) (6), 503 - 515, English
    [Refereed]
    Book review

  • Dendritic Cells in Atherogenesis: Possible Novel Targets for Prevention of Atherosclerosis
    Masafumi Takeda, Tomoya Yamashita, Naoto Sasaki, Ken-ichi Hirata
    Atherosclerosis has been recognized as an inflammatory disease of the arterial wall, involving innate and adaptive immunity. Effector T cells are differentiated from naive T cells stimulated by antigen-presenting cells such as macrophages and dendritic cells (DCs) and play critical roles in atherogenesis. Accumulating evidence revealed that several subsets of regulatory T cells (Tregs) inhibit atherosclerotic lesion formation via inhibiting the inflammatory response of effector T cells. In addition, the contribution of DCs to atherogenesis has been demonstrated. DCs have different functions for either stimulating or inhibiting T cell function depending on their origin and maturation stage. In particular, immature DCs, which have potential for inducing Tregs and inhibiting effector T cells, are sometimes called 'tolerogenic DCs' and suppress immune responses. Epidemiological studies have highlighted the increasing prevalence of vitamin D-3 deficiency and its association with increased risks of cardiovascular diseases. Some studies have raised interest in the immunomodulatory properties of vitamin D-3 beyond its well-established role in bone and calcium metabolism. The active form of vitamin D-3 (calcitriol) induces Tregs and tolerogenic DCs, which are both involved in maintaining immunologic tolerance to self and harmless antigens. Interestingly, recent evidence suggested that DCs in the intestinal immune system are involved in inducing Tregs; modulating the function of DCs and Tregs in the intestinal immune system might have beneficial effects on atherosclerosis. In this review, we focus on the function of DCs in vascular diseases and discuss vitamin D-3 therapy for the prevention of atherosclerosis. J Atheroscler Thromb, 2012; 19: 953-961.
    JAPAN ATHEROSCLEROSIS SOC, 2012, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(11) (11), 953 - 961, English
    [Refereed]
    Book review

  • 心房細動および心房粗動に対するカテーテルアブレーション後に心室細動を発症した一例
    杉崎陽一郎, 藤原竜童, 今西純一, 山下智也, 武居明日美, 石田達郎, 吉田明弘, 志手淳也, 川合宏哉, 平田健一
    2011, 日本循環器学会近畿地方会(Web), 112th

  • Anti-inflammatory and immune modulation therapy against atherosclerosis
    山下 智也, 平田 健一
    日本臨床社, Jan. 2011, Japanese journal of clinical medicine, 69(1) (1), 168 - 172, Japanese

  • Oral Administration of an Active Form Vitamin D-3 Decreases Atherosclerosis in Mice via Modulating Immune Cell Phenotypes and Functions
    Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Kenji Nakajima, Tomoyuki Kita, Ken-ichi Hirata
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2009, CIRCULATION, 120(18) (18), S1067 - S1068, English
    Summary international conference

  • 知っておきたい血管医学用語(27)Dendritic cell(樹状細胞)
    山下 智也, 平田 健一
    先端医学社, Jan. 2009, Vascular medicine, 5(1) (1), 66 - 70, Japanese

  • PLASMA TETRAHYDROBIOPTERIN DIHYDROBIOPTERIN RATIO: A POSSIBLE MARKER OF ENDOTHELIAL DYSFUNCTION
    Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Kenji Nakajima, Naoto Sasaki, Ken-ichi Hirata, Seinosuke Kawashima
    KARGER, 2009, JOURNAL OF VASCULAR RESEARCH, 46, 158 - 158, English
    Summary international conference

  • Wulf Palinski, Tomoya Yamashita, Stefan Freigang, Claudio Napoli
    It is increasingly recognized that the in utero environment is an important determinant of adult disease, and extensive epidemiological evidence links dysmetabolic conditions during pregnancy with increased hypertension, cardiovascular disease, and diabetes later in life. The original Barker Hypothesis focused on low birth weight as the primary indicator of postnatal risk, but low birth weight may arise from other, nonmetabolic conditions. This has impeded the identification of developmental programming mechanisms. More recently, the focus has shifted to the impact of specific maternal risk factors, such as obesity, metabolic syndrome, and diabetes, on cardiovascular risk in offspring. Inflammation plays a central role in these maternal conditions as well as in offspring atherogenesis, and two key factors that influence inflammation, maternal hypercholesterolemia and maternal immune mechanisms, have been shown to affect the developmental programming of atherosclerosis. Maternal hypercholesterolemia in pregnancy, even if only temporary, is associated with increased fatty streak formation in human fetal arteries and accelerated progression of atherosclerosis in normocholesterolemic children. Conversely, immunization of experimental animals with oxidized low-density lipoprotein cholesterol, an antigen prevalent in atherosclerotic lesions, inhibits the progression of atherosclerosis in the offspring of hypercholesterolemic mothers. These findings indicate it is possible, in principle, to program postnatal immune responses and to reduce atherosclerosis, and potentially other immunomodulated diseases, by targeted maternal immunomodulation.
    BLACKWELL PUBLISHING, Dec. 2007, NUTRITION REVIEWS, 65(12) (12), S182 - S187, English
    [Refereed]
    Introduction scientific journal

  • Oral Anti-CD3 antibody treatment induces CD4+LAP+ regulatory T cells and ameliorates the development of atherosclerosis in mice
    Naoto Sasaki, Tomoya Yamashita, Hideto Tawa, Masafumi Takeda, Tomoya Masano, Masakazu Shinohara, Ryuji Toh, Seirm Kobayashi, Ken-Ichi Hirata
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2007, CIRCULATION, 116(16) (16), 146 - 146, English
    Summary international conference

  • Atherosclerotic plaque imaging using phase-contrast X-ray computed tomography
    Masakazu Shinohara, Tomoya Yamashita, Hideto Tawa, Masafurni Takeda, Naoto Sasaki, Akihisa Takeuchi, Takuji Ohigashi, Kunio Shinohara, Ken-ichi Hirata, Seinosuke Kawashima, Mitsuhiro Yokoyama, Atsushi Momose
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2007, CIRCULATION, 116(16) (16), 769 - 769, English
    [Refereed]
    Summary international conference

  • 【適切な高脂血症診療の実践のために】 高脂血症治療薬の種類と薬理作用 その他の高脂血症治療薬
    Yamashita Tomoya
    Jul. 2007, 綜合臨床, 56巻, 7, pp. 2298-2302, Japanese
    Introduction scientific journal

  • 【メタボリックシンドロームup to date】 基礎 血管内皮
    Yamashita Tomoya
    Jun. 2007, 日本医師会雑誌, 136巻, , pp. 104-106, Japanese
    Introduction scientific journal

  • 3 How to Regulate the Inflammation in Atherogenesis : Novel Vaccine Strategies for Prevention of Atherosclerosis(A New Era in Atherosclerosis Research, The 71st Annual Scientific Meeting of the Japanese Circulation Society)
    Yamashita Tomoya, Palinski Wulf, Yokoyama Mitsuhiro
    Japanese Circulation Society, 01 Mar. 2007, Circulation journal : official journal of the Japanese Circulation Society, 71, 13 - 13, English

  • 【スタチンの可能性を探る】 治す スタチンとの併用療法はなにが最適か
    YAMASHITA TOMOYA
    Mar. 2007, Heart View, 11巻, 3号, pp. 306-310, Japanese
    Introduction scientific journal

  • 診断と治療 最近の進歩 虚血性心疾患 EPAの効果
    YAMASHITA TOMOYA
    Jan. 2007, Annual Review循環器, 2007巻, pp. 115-120, Japanese
    Introduction scientific journal

  • Augmentation of vascular remodeling due to uncoupled eNOS in diabetes
    Naoto Sasaki, Seinosuke Kawashima, Masafumi Takeda, Tomoya Masano, Tomofumi Takaya, Masakazu Shinohara, Rio Shiraki, Ryuji Toh, Seimi Kobayashi, Tomoya Yamashita, Mitsuhiro Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2006, CIRCULATION, 114(18) (18), 152 - 152, English
    Summary international conference

  • An X-ray diffraction study on mouse cardiac cross-bridge function in vivo: Effects of adrenergic beta-stimulation
    R Toh, N Yagi, M Shinohara, T Takaya, S Masuda, T Yamashita, S Kawashima, M Yokoyama
    CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, Dec. 2005, JOURNAL OF CARDIAC FAILURE, 11(9) (9), S292 - S292, English
    Summary international conference

  • Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries
    M Shinohara, S Kawashima, T Yamashita, T Takaya, R Toh, T Ishida, T Ueyama, N Inoue, KI Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2005, CIRCULATION, 112(17) (17), U225 - U225, English
    Summary international conference

  • An x-ray diffraction study on mouse cardiac cross-bridge function in vivo: Effects of adrenergic beta-stimulation
    R Toh, N Yagi, M Shinohara, T Takaya, T Yamashita, S Kawashima, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2005, CIRCULATION, 112(17) (17), U325 - U325, English
    Summary international conference

  • Telmisartan reduces atherosclerotic lesion formation by decreasing superoxide generation in apolipoprotein E-deficient mice
    T Takay, S Kawashima, M Shinohara, T Yamashita, N Inoue
    ELSEVIER IRELAND LTD, Apr. 2005, ATHEROSCLEROSIS SUPPLEMENTS, 6(1) (1), 45 - 45, English
    Summary international conference

  • In vivo evaluation of X-ray diffraction from the left ventricular wall of mouse hearts
    R Toh, N Yagi, S Kawashima, T Yamashita, M Shinohara, T Takaya, S Masuda, M Yokoyama
    ELSEVIER SCIENCE INC, Feb. 2005, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 45(3) (3), 257A - 257A, English
    Summary international conference

  • Increased GTP-cyclohydrolase I expression but not vitamin C treatment restored accelerated atherosclerotic lesion formation in apolipoprotein E-deficient mice overexpressing endothelial nitric oxide synthase
    T Takaya, S Kawashima, T Yamashita, M Shinohara, K Hirata, N Inoue, KM Channon, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2004, CIRCULATION, 110(17) (17), 179 - 179, English
    Summary international conference

  • Overexpression of endothelial nitric oxide synthase deteriorates vascular remodeling in apoE-deficient mice
    M Shinohara, S Kawashima, T Takaya, T Yamashita, N Inoue, KI Hirata, M Yokoyama
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Aug. 2004, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 11(1) (1), 63 - 64, English
    Summary international conference

  • GTPCH I overexpression decreases atherosclerotic lesion formation in apolipoprotein E-deficient/eNOS transgenic mice
    T Takaya, S Kawashima, T Yamashita, M Shinohara, N Inoue, KI Hirata, K Channon, M Yokoyama
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Aug. 2004, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 11(1) (1), 64 - 64, English
    Summary international conference

  • 【血管研究の最先端と治療への展開 血管新生・血管病態の分子メカニズムから現実となった新時代の臨床応用まで】 治療への展開 動脈硬化ワクチン療法 基礎研究から臨床応用へむけて
    篠原正和, YAMASHITA,Tomoya, YOKOYAMA, Mitsuhiro
    May 2004, 実験医学, 22巻, 8号, pp. 1215-1220, Japanese
    Introduction scientific journal

  • 【血管の先進映像医学】 放射光微小血管造影装置による再生血管の可視化
    YAMASHITA,Tomoya, 高谷具史, KAWASHIMA, Seinosuke, 梅谷啓二, 篠原正和, YOKOYAMA, Mitsuhiro
    Feb. 2004, 血管医学, 5巻, 1号, pp. 11-16, Japanese
    Introduction scientific journal

  • Xenogenic Macrophage Immunization as a Vaccine Reduces Atherosclerosis in Apolipoprotein E Knockout Mice
    Yamashita Tomoya, Kawashima Seinosuke, Hirase Tetsuaki, Shinohara Masakazu, Takaya Tomofumi, Inoue Nobutaka, Hirata Kenichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 01 Mar. 2003, Circulation journal : official journal of the Japanese Circulation Society, 67, 398 - 398, English

  • Transplantation of cardiotropin-1-expressing myoblasts to the left ventricular wall prevents the transition from compensatory hypertrophy to congestive heart failure in Dahl salt-sensitive hypertensive rats
    R Toh, S Kawashima, M Kawai, T Sakoda, T Nakai, S Kobayashi-Satomi, M Ozaki, T Yamashita, N Inoue, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2002, CIRCULATION, 106(19) (19), 30 - 30, English
    Summary international conference

  • Supplementation of tetrahydrobiopterin inhibits atherosclerosis in apolipoprotein E-deficient mice
    M Ozaki, S Kawashima, T Yamashita, M Namiki, T Hirase, N Inoue, K Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2002, CIRCULATION, 106(19) (19), 70 - 70, English
    Summary international conference

  • Xenogenic macrophage immunization as a vaccine reduces atherosclerosis in apolipoprotein E knockout mice
    T Yamashita, S Kawashima, M Ozaki, M Shinohara, N Inoue, K Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2002, CIRCULATION, 106(19) (19), 182 - 182, English
    Summary international conference

  • Development of In Vivo Microangiography System Using Synchrotron Radiation : Angiographic Evaluation of Mouse Peripheral and Coronary Arteries
    YAMASHITA T, KAWASHIMA S, OZAKI M, NAMIKI M, UMETANI K, INOUE N, HIRATA K, MORI H, YOKAYAMA M
    25 Aug. 2002, 脈管学, 42(8) (8), 493 - 498, Japanese

  • Two Faces of eNOS in Vascular Remodeling
    KAWASHIMA S., OZAKI M., YAMASHITA T., NAMIKI M., YOKOYAMA M.
    25 May 2002, 脈管学, 42(5) (5), 291 - 296, Japanese

  • In Vivo Mouse Coronary Angiography Using Synchrotron Radiation Microangiography
    Namiki Masayuki, Kawashima Seinosuke, Yamashita Tomoya, Ozaki Masanori, Inoue Nobutaka, Hirata Kenichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 31 Mar. 2002, Circulation journal : official journal of the Japanese Circulation Society, 66, 289 - 289, English

  • A HMG-CoA Reductase Inhibitor Reduces Stroke Events and Mortality In Stroke-Prone Spontaneous Hypertensive Rats
    Yamashita Tomoya, Kawashima Seinosuke, Miwa Yoichi, Ozaki Masanori, Namiki Masayuki, Inoue Nobutaka, Hirata Ken-ichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 31 Mar. 2002, Circulation journal : official journal of the Japanese Circulation Society, 66, 520 - 520, English

  • Supplement of tetrahydrobiopterin inhibits atherosclerosis in apoE-deficient mice
    Ozaki Masanori, Kawashima Seinosuke, Yamashita Tomoya, Namiki Masayuki, Hirase Tetsuaki, Inoue Nobutaka, Hirata Ken-ichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 31 Mar. 2002, Circulation journal : official journal of the Japanese Circulation Society, 66, 411 - 411, English

  • A HMG-CoA Reductase Inhibitor Reduces Hypertensive Nephrosclerosis In Stroke Prone-SHR
    Yamashita Tomoya, Kawashima Seinosuke, Miwa Yoichi, Ozaki Masanori, Namiki Masayuki, Hirase Tetsuaki, Inoue Nobutaka, Hirata Ken-ichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 31 Mar. 2002, Circulation journal : official journal of the Japanese Circulation Society, 66, 638 - 638, English

  • Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion development in apoE-deficient mice
    Ozaki Masanori, Kawashima Seinosuke, Yamashita Tomoya, Namiki Masayuki, Hirase Tetsuaki, Inoue Nobutaka, Hirata Ken-ichi, Yokoyama Mitsuhiro
    Japanese Circulation Society, 31 Mar. 2002, Circulation journal : official journal of the Japanese Circulation Society, 66, 209 - 209, English

  • 内皮細胞機能に注目した血管病治療 (特集 微小循環障害) -- (微小循環基礎研究のUp date)
    山下 智也, 横山 光宏
    現代医療社, 2002, 現代医療, 34(4) (4), 2733 - 2738, Japanese

  • Mouse coronary angiograph using synchrotron radiation microangiography
    T Yamashita, S Kawashima, M Ozaki, M Namiki, T Hirase, N Inoue, K Hirata, K Umetani, K Sugimura, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Jan. 2002, CIRCULATION, 105(2) (2), E3 - E4, English
    Others

  • Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion development in ApoE-deficient mice
    M Ozaki, S Kawashima, T Yamashita, M Namiki, T Nakai, T Hirase, N Inoue, KI Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 2001, CIRCULATION, 104(17) (17), 273 - 273, English
    Summary international conference

  • Endogeneous nitric oxide attenuates chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling: A study using endothelial nitric oxide synthase overexpressing mice
    M Ozaki, S Kawashima, T Yamashita, Y Ohashi, N Inoue, K Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 1999, CIRCULATION, 100(18) (18), 114 - 114, English
    Summary international conference

  • Resistance to endotoxin shack in transgenic mice overexpressing endothelial nitric oxide synthase
    T Yamashita, S Kawashima, M Ozaki, Y Ohashi, T Ishida, N Inoue, K Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 1999, CIRCULATION, 100(18) (18), 113 - 113, English
    Summary international conference

  • Nitric oxide overproduced by endothelial cells prevents vascular remodeling in the mouse carotid artery
    T Yamashita, S Kawashima, M Ozaki, Y Ohashi, S Takeuchi, T Ishida, N Inoue
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 1999, CIRCULATION, 100(18) (18), 3 - 3, English
    Summary international conference

  • Reduced relaxations to NO/cGMP-mediated vasodilators in transgenic mice overexpressing endothelial nitric oxide synthase
    T Yamashita, Y Ohashi, S Kawashima, M Ozaki, T Ishida, T Sakoda, N Inoue, K Hirata, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 1998, CIRCULATION, 98(17) (17), 44 - 44, English
    Summary international conference

  • Unchanged neurohumoral regulatory factors of blood pressure in endothelial cell nitric oxide synthase-overexpressing mice
    Y Ohashi, S Kawashima, T Yamashita, M Ozaki, T Sakoda, N Inoue, M Yokoyama
    LIPPINCOTT WILLIAMS & WILKINS, Oct. 1998, CIRCULATION, 98(17) (17), 4 - 5, English
    Summary international conference

  • Generation of transgenic mice overexpressing endothelial cell nitric oxide synthase in the vascular wall
    Y Ohashi, S Kawashima, T Yamashita, K Hirata, S Mikami, T Ishida, T Sakoda, N Inoue, M Yokoyama
    AMER HEART ASSOC, Oct. 1997, CIRCULATION, 96(8) (8), 3073 - 3073, English
    Summary international conference

  • Lysophosphatidylcholine inhibits basic FGF-mediated proliferation and migration of vascular endothelial cells via the inhibition of MAP kinase activation
    Y Rikitake, S Kawashima, T Yamashita, T Ueyama, A Matsuura, N Inoue, M Yokoyama
    AMER HEART ASSOC, Oct. 1997, CIRCULATION, 96(8) (8), 2816 - 2816, English
    Summary international conference

■ Books And Other Publications
  • Current Therapy in Cardiovascular Diseases
    Tomoya Yamashita, Ken-ichi Hirata
    Contributor, Gut microbiota in cardiovascular diseases, 南江堂, Jan. 2020

  • Atherosclerosis in clinics
    山下智也, 平田健一
    Contributor, Gut microbiota, 日本医師会, Oct. 2019

  • Gut microbiota ~Another organ for controlling human health and disease~
    山下智也
    Contributor, 腸内細菌叢のバランス異常と疾患 循環器疾患, 羊土社, Sep. 2019

  • Molecular Cardiology for developing new clinical medicine
    山下智也, 平田健一
    Contributor, 腸から動脈硬化を予防する, 南山堂, Mar. 2019

  • Gut and oral microbiota in systemic diseases
    Tomoya Yamashita, Ken-ichi Hirata
    Contributor, 動脈硬化と腸内細菌, シーエムシー出版, Dec. 2015, Japanese
    Scholarly book

  • Annual Review糖尿病・代謝・内分泌2013
    山下智也, 平田健一
    Contributor, 腸内細菌と動脈硬化, 中外医学社, 2013

  • New strategies in protection of vasculature
    Yamashita Tomoya
    Contributor, 血管障害の背景 炎症, ライフサイエンス, May 2007, Japanese
    Scholarly book

  • Oxidative stress an cardiovascular diseases
    YAMASHITA TOMOYA
    Contributor, 炎症, 日本医学出版, Mar. 2007, Japanese
    Scholarly book

  • Metabolic syndrome up to date
    Yamashita Tomoya
    Contributor, 血管内皮, 日本医師会, 2007, Japanese
    Scholarly book

  • Annual Review Cardiovascular Disease 2007
    Yamashita Tomoya
    Contributor, 診断の進歩 虚血性心疾患 EPAの効果, 中外医学社, 2007, Japanese
    Scholarly book

■ Lectures, oral presentations, etc.
  • Intestinal microbiota in heart failure
    Tomoya Yamashita, Tokiko Tabata, Takuo Emoto, Tomohiro Hayashi, Hikaru Watanabe, Tomoya Takahashi, Naofumi Yoshida, Yoshihiro Saito, Takuji Yamada, Ken-ichi Hirata
    84th Annual Scientific Meeting of Japanese Circulatory Society, Jul. 2020, Japanese

  • Gut microbiome and atherosclerosis
    Tomoya Yamashita
    第60回日本神経内科学会学術大会, May 2019, English
    [Invited]
    Nominated symposium

  • 糖尿病薬の腸内細菌への影響と腸内細菌叢から見た動脈硬化予防
    YAMASHITA TOMOYA
    第53回糖尿病のの進歩, Mar. 2019, Japanese, 日本糖尿病学会, 青森, 腸内細菌と循環器疾患との関係, Domestic conference
    [Invited]
    Invited oral presentation

  • 冠動脈疾患患者大腸フローラモデルによる候補投与物の調査
    SASAKI KENGO, 吉田 尚史, SASAKI DAISUKE, OSAWA RO, YAMASHITA TOMOYA, 近藤 昭彦
    日本農芸化学会2019年度大会, Mar. 2019, Japanese, 東京農業大学 世田谷キャンパス, Domestic conference
    Poster presentation

  • The Correlation between Circulating Intermediate CD14++CD16+Monocytes and Atrial Electrical Remodeling in Atrial Fibrillation Patients
    Hideya Suehiro, Koji Fukuzawa, Tomoya Yamashita, Naofumi Yoshida, Kunihiko Kiuchi, Mitsuru Takami, Jun Kurose, Tomomi Akita, Yu-ichi Nagamatsu, Makoto Takemoto, Toshihiro Nakamura, Jun Sakai, Atsusuke Yatomi, Kenichi Hirata
    第83回日本循環器学会学術集会, Mar. 2019, Japanese, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Gut microbiome, novel therapeutic targets for preventing atherosclerotic cardiovascular diseases
    YAMASHITA TOMOYA, 吉田 尚史, HIRATA KENICHI
    第83回日本循環器学会学術集会, Mar. 2019, Japanese, 日本循環器学会, 神奈川, Gut microbiome could be therapeutic targets for prevention of cardiovascular disease, Domestic conference
    Public symposium

  • 腸内細菌叢と循環器疾患〜性差からの考察を加えて〜
    YAMASHITA TOMOYA
    第12回日本性差医学・医療学会学術集会, Jan. 2019, Japanese, 日本性差医学・医療学会, 埼玉, 腸内細菌と循環器疾患との関係, Domestic conference
    [Invited]
    Invited oral presentation

  • 冠動脈疾患と心不全における心臓腸管連関
    YAMASHITA TOMOYA, 林 友鴻, HIRATA KENICHI
    第22回日本心不全学会学術集会, Oct. 2018, Japanese, 日本心不全学会, 東京, 腸内細菌と循環器疾患との関係, Domestic conference
    Public symposium

  • Gut microbiome composition and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure
    林 友鴻, YAMASHITA TOMOYA, HIRATA KENICHI
    第22回日本心不全学会学術集会, Oct. 2018, English, 日本心不全学会, 東京, We investigate the relationship between the gut microbiome and heart failure., Domestic conference
    Oral presentation

  • Gut microbiome composition and plasma microbial metabolites in patients with heart failure
    林 友鴻, YAMASHITA TOMOYA, 吉田 尚史, 田畑 論子, IRINO YASUHIRO, TOH RYUJI, HIRATA KENICHI
    第2回日本循環器学会基礎研究フォーラム, Sep. 2018, Japanese, 日本循環器学会, 奈良, We investigate the relationship between the gut microbiome and heart failure., Domestic conference
    Poster presentation

  • Bacteroides vulgatus と Bacteroides doreiは腸内細菌のLPS産生を制御し動脈硬化を抑制する
    吉田 尚史, YAMASHITA TOMOYA, 江本 拓央, 渡邊 日佳流, 林 友鴻, 田畑 論子, 佐々木直人, 山田 拓司, HIRATA KENICHI
    第66回日本心臓病学会, Sep. 2018, Japanese, 日本心臓病学会, 大阪, Bacteroidesが動脈硬化を抑制する。, Domestic conference
    Oral presentation

  • Bacteroides inhibits atherosclerosis by regulating gut microbial LPS production
    吉田 尚史, YAMASHITA TOMOYA, 江本 拓央, 渡邊 日佳流, 林 友鴻, 田畑 論子, HIRATA KENICHI
    第2回日本循環器学会基礎研究フォーラム, Sep. 2018, English, 日本循環器学会, 奈良, Bacteroides inhibits atherosclerosis., Domestic conference
    Poster presentation

  • 腸内細菌優勢菌であるBacteroidesは糞便LPS値を低下させる事で動脈硬化を抑制する
    吉田 尚史, YAMASHITA TOMOYA, 江本 拓央, 渡邊 日佳流, 林 友鴻, 田畑 論子, 小澤 元希, 山田 拓司, HIRATA KENICHI
    第50回日本動脈硬化学会, Jul. 2018, Japanese, 日本動脈硬化学会, 大阪, Bacteroidesが動脈硬化を抑制する。, Domestic conference
    Poster presentation

  • 紫外線B波照射はCD4陽性Foxp3陽性制御性T細胞を増幅し、アンギオテンシンII誘導性マウス大動脈瘤の形成を抑制する
    林 友鴻, SASAKI NAOTO, YAMASHITA TOMOYA, 溝口 泰司, 江本 拓央, Hilman Zulkifli Amin, 淀井(眞弓) 景子, 松本 卓也, 笠原 和之, 吉田 尚史, 田畑 論子, 北野 尚樹, FUKUNAGA ATSUSHI, NISHIGORI CHIKAKO, 力武 良行, HIRATA KENICHI
    第50回日本動脈硬化学会総会・学術集会, Jul. 2018, Japanese, 日本動脈硬化学会, 大阪, UVBが腹部大動脈瘤を抑制することを報告した, Domestic conference
    Oral presentation

  • The correlation between circulating intermediate CD14++CD16+monocytes and atrial electrical remodeling in AF patients
    Hideya Suehiro, Koji Fukuzawa, Tomoya Yamashita, Naofumi Yoshida, Kunihiko Kiuchi, Mitsuru Takami, Jun Kurose, Tomomi Akita, Yu-ichi Nagamatsu, Makoto Takemoto, Kenichi Hirata
    第65回日本不整脈心電学会学術大会, Jul. 2018, English, 日本不整脈心電学会, 東京, Domestic conference
    Poster presentation

  • Bacteroides vulgatus と Bacteroides doreiは腸内細菌のLPS産生を制御し動脈硬化を抑制する
    吉田 尚史, YAMASHITA TOMOYA, 江本 拓央, 渡邊 日佳流, 林 友鴻, 田畑 論子, 小澤 元希, 山田 拓司, HIRATA KENICHI
    第22回腸内細菌学会, May 2018, Japanese, 腸内細菌学会, 東京, Bacteroidesが動脈硬化を抑制する。, Domestic conference
    Oral presentation

  • Gut microbiota and their relevant metabolites could be novel biomarkers and innovative therapeutic targets of chronic heart failure
    林 友鴻, Yamashita Tomoya, Hirata Ken-ichi
    The 82th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2018, Japanese, The Japanese Circulation Society, 大阪, We investigate the relationship between the gut microbiota and heart failure., Domestic conference
    Public symposium

  • Alterations of gut microbiota composition and microbiota-associated metabolites in chronic heart failure
    林 友鴻, Yamashita Tomoya, 吉田 尚史, 田畑 論子, 江本 拓央, 佐々木 直人, 溝口 泰司, Hilman Zulkifli Amin, Irino Yasuhiro, Toh Ryuji, Shinohara Masakazu, Hirata Ken-ichi
    The 82th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2018, Japanese, The Japanese Circulation Society, 大阪, We investigate the relationship between the gut microbiota and heart failure., Domestic conference
    Oral presentation

  • The role of gut microbiota in coronary artery diseases and heart failure
    林 友鴻, Yamashita Tomoya, Hirata Ken-ichi
    Cardiovascular and metabolic week 2017, Dec. 2017, Japanese, The Japanese Vascular Biology and Medicine Organization, The Society of Cardiovascular Endocrinology and Metabolism, and International Society for Heart Research, 大阪, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    [Invited]
    Nominated symposium

  • Prevention of atherosclerosis vis modulating the inflammatory process; Intestinal immunity and gut microbiota in atherosgenesis
    Yamashita Tomoya
    The 6th International Congress on Lipid & Atherosclerosis, Sep. 2017, English, Korean Society of Lipid and Atherosclerosis, ソウル, 韓国, The relationship between the gut microbiota and intestinal immunity, International conference
    [Invited]
    Nominated symposium

  • Gut microbiota and atherosclrosis
    Yamashita Tomoya, Hirata Ken-ichi
    The 49th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2017, Japanese, The Japan Atherosclerosis Society, 広島, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    Public symposium

  • 紫外線照射は制御性T細胞の誘導を介して心筋梗塞の予後を改善させる
    佐々木 直人, 溝口 泰司, Fukunaga Atsushi, Nishigori Chikako, Yamashita Tomoya, Hirata Ken-ichi, 力武 良行
    第39回日本光医学・光生物学会, Jul. 2017, Japanese, 日本光医学・光生物学会, 名古屋, Domestic conference
    Oral presentation

  • A new ultraviolet-based immunomodulatory approach to abdominal aortic aneurysm
    林 友鴻, 佐々木 直人, Yamashita Tomoya, 溝口 泰司, Hilman Zulkifli Amin, 江本 拓央, 吉田 尚史, 田畑 論子, Hirata Ken-ichi
    The 49th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2017, Japanese, The Japan Atherosclerosis Society, 広島, UVB irradiation to the skin inhibits abdominal aortic aneurysm in mice, Domestic conference
    Poster presentation

  • 紫外線照射による動脈硬化抑制効果の検討
    佐々木 直人, 林 友鴻, Fukunaga Atsushi, Nishigori Chikako, Yamashita Tomoya, Hirata Ken-ichi, 力武 良行
    第39回日本光医学・光生物学会, Jul. 2017, Japanese, 日本光医学・光生物学会, 名古屋, Domestic conference
    Oral presentation

  • Gut microbiota and atherothrombosis
    Yamashita Tomoya, Hirata Ken-ichi
    The 39th Congress of the Japanese Society on thrombosis and Hemostasis, Jun. 2017, Japanese, Japan Society on Thrombosis and Hemostasis, 名古屋, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    [Invited]
    Nominated symposium

  • Gut microbiota and Cardiovascular diseases
    Yamashita Tomoya, Hirata Ken-ichi
    21th Annual Meeting of Intestinal Microbiology, Jun. 2017, Japanese, Japan Bifidus Foundation, 神戸, 日本, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    [Invited]
    Nominated symposium

  • Gut microbiota and coronary artery diseases
    Yamashita Tomoya, Hirata Ken-ichi
    27th Annual Meeting of the Japan Cytometry Society, Jun. 2017, Japanese, Japan Cytometry Society, 神戸, 日本, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    [Invited]
    Nominated symposium

  • Gut microbiota and Cardiovascular diseases
    Yamashita Tomoya, Hirata Ken-ichi
    The 17th Annual Meeting of NO Society of Japan, May 2017, Japanese, NO society of Japan, 徳島, We investigate the relationship between the gut microbiota and cardiovascular disease., Domestic conference
    [Invited]
    Nominated symposium

  • Ultraviolet B Irradiation Inhibits the Development of Angiotensin II-Induced Abdominal Aortic Aneurysm Formation by Regulating Immuno-Inflammatory Responses
    林 友鴻, Sasaki Naoto, Yamashita Tomoya, 江本 拓央, 溝口 泰司, 吉田 尚史, 田畑 論子, Hilman Zulkifli Amin, Hirata Ken-ichi
    The 81st Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2017, English, The Japanese Circulation Society, 金沢, UVB irradiation to the skin inhibits abdominal aortic aneurysm in mice, Domestic conference
    Oral presentation

  • Ultraviolet B exposure improves survival after myocardial infarction in mice
    Taiji Mizoguchi, Sasaki Naoto, Yamashita Tomoya, Hilman Amin, Naofumi Yoshida, Tomohiro Hayashi, Takuo Emoto, Hirata Ken-ichi
    The 81st Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2017, English, The Japanese Circulation Society, 金沢, We reported Ultraviolet B exposure improves survival after myocardial infarction in mice, Domestic conference
    Oral presentation

  • Gut Microbiota as Residual Risks and Novel Therapeutic Targets in Coronary Artery Disease
    Yamashita Tomoya, Hirata Ken-ichi
    The 81st Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2017, Japanese, The Japanese Circulation Society, 金沢, Gut microbiota is associated with coronary artery disease and therapeutic targets., Domestic conference
    Public symposium

  • Prevention of atherosclerosis from gut microbiota
    Yamashita Tomoya, Hirata Ken-ichi
    The 46th Annual Meeting of japanese Society for Circulation Resesrch, Feb. 2017, Japanese, The japanese Society for Circulation Research, 沖縄, Gut microbiota is associated with coronary artery disease., Domestic conference
    [Invited]
    Nominated symposium

  • Ultraviolet B Exposure Limits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice
    林 友鴻, Sasaki Naoto, Yamashita Tomoya, 江本 拓央, 溝口 泰司, 吉田 尚史, 田畑 論子, Hilman Zulkifli Amin, Hirata Ken-ichi
    The 24th Annual Meeting of the Japanese Vascular Biology and Medicine Organization, Dec. 2016, Japanese, The Japanese Vascular Biology and Medicine Organization, 長崎, UVB irradiation to the skin inhibits abdominal aortic aneurysm in mice, Domestic conference
    [Invited]
    Nominated symposium

  • Gut microbiota and cardiovascular disease
    Yamashita Tomoya
    The41st Annual Meeting of Japanese Society for Microcirculation, Sep. 2016, Japanese, The Japanese Society for Microcirculation, 東京, Gut microbiota is associated with coronary artery disease., Domestic conference
    [Invited]
    Nominated symposium

  • Role of regulatory T cells in atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Hirata Ken-ichi
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, We clarified the role of regulatory T cells in atherosclerosis., Domestic conference
    [Invited]
    Nominated symposium

  • Role of gut microbiota in prevention of heart disease
    Yamashita Tomoya, Hirata Ken-ichi
    The 22nd Annual Meeting of the Japanese Association of Cardiac Rehabilitation, Jul. 2016, Japanese, The Japanese Association of Cardiac Rehabilitation, 東京, Gut microbiota is associated with coronary artery disease., Domestic conference
    [Invited]
    Nominated symposium

  • Investigation of the effect of UVB irradiation on abdominal aortic aneurysm
    林 友鴻, Sasaki Naoto, 江本 拓央, 溝口 泰司, 吉田 尚史, Hilman Zulkifli Amin, 松本 卓也, Yamashita Tomoya, Hirata Ken-ichi
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, Low-dose UVB irradiation to the skin reduces abdominal aortic aneurysm, Domestic conference
    Poster presentation

  • Oral administration of the Lactic Acid Bacterium Pediococuss acidililactici attenuates atherosclerosis via inducing tolerogenic dedritic cells in mice
    Taiji Mizoguchi, Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Takuo Emoto, Takuya Matsumoto, Tomohiro Hayashi, Hirata Ken-ichi
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, We reported R037-treatment attenuated the progression of atherosclerosis in mice., Domestic conference
    Poster presentation

  • Intestinal immunity and gut microbiota in atherogenesis
    Yamashita Tomoya
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, Gut microbiota is associated with coronary artery disease., Domestic conference
    Oral presentation

  • Dysbiosis of gut microbiota in coronary artery diesease patients
    Takuo Emoto, Yamashita Tomoya, Sasaki Naoto, Tomohiro Hayashi, Takuya Matsumoto, Taiji Mizoguchi, Naofumi Yoshida, Hilman Zulkifli Amin, Hikaru Watanabe, Takuji Yamada, Hirata Ken-ichi
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, We could demonstrate a specific characteristic profile of gut microbiota in CAD patients., Domestic conference
    Poster presentation

  • Co-inhibitory molecule CTLA-4 regulates atherosclerosis by suppressing T cell and dendritic cell activation in mice
    Sasaki Naoto, Takuya Matsumoto, Takuo Emoto, Taiji Mizoguchi, Tomohiro Hayashi, Yamashita Tomoya, Hirata Ken-ichi
    The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2016, Japanese, The Japan Atherosclerosis Society, 東京, CTLA-4 prevents atherosclerosis in mice, Domestic conference
    Poster presentation

  • Gut microbiota and cardiovascular disease
    Yamashita Tomoya
    Annual meeting of Japan Association for Omics-based Medicine, Jun. 2016, Japanese, Japan Association for Omics-based Medicine, 東京, Gut microbiota is associated with coronary artery disease., Domestic conference
    [Invited]
    Nominated symposium

  • Gut microbiota and atherosclerosis
    Yamashita Tomoya, Hirata Ken-ichi
    Annual meeting of the Japan endocrine society, Apr. 2016, Japanese, The Japan Endocine Society, 京都, Gut microbiota is associated with coronary artery disease., Domestic conference
    [Invited]
    Nominated symposium

  • Ultraviolet B exposure prevents atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Takuo Emoto, Takuya Matsumoto, Taiji Mizoguchi, Tomohiro Hayashi, Hirata Ken-ichi
    80th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2016, English, The Japanese Circulation Society, 仙台, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., Domestic conference
    Poster presentation

  • Overexpression of CTLA-4 prevents atherosclerosis by suppressing T cell activation in mice
    Takuya Matsumoto, Sasaki Naoto, Takuo Emoto, Taiji Mizoguchi, Tomohiro Hayashi, Yamashita Tomoya, Ken-ici Hirata
    80th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2016, English, The Japanese Circulation Society, 仙台, CTLA-4 prevents atherosclerosis in mice, Domestic conference
    Oral presentation

  • Oral administration of the Lactic Acid Bacterium Pediococcus acidilactici attenuates atherosclerosis via inducing tolerogenic dendritic cells in mice
    Taiji Mizoguchi, Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Takuya Matsumoto, Takuo Emoto, Tomohiro Hayashi, Keiko Yodoi, Naoki Kitano, Hirata Ken-ichi
    80th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2016, English, the Japanese Circulation Society, 仙台, Administration of lactic acid bacterium prevented atherosclerosis and could be an atractive aproach for prevention of atherclerosis., Domestic conference
    Poster presentation

  • Gut microbiota could be a predictor of the risk of coronary atherosclerosis.
    Takuo Emoto, Yamashita Tomoya, Toshio Kobayashi, Sasaki Naoto, Kazuyuki Kasahara, Keiko Yodoi, Takuya Matsumoto, Taiji Mizoguchi, Tomohiro Hayashi, Hirata Ken-ichi
    80th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2016, English, The Japanese Circulation Society, 仙台, Data mining analysis clarified characteristic patterns of gut microbiota to distinguish CAD patients from Ctrls, suggesting a clinical potential to predict the incidence of CAD., Domestic conference
    Oral presentation

  • Gut microbiota could be a diagnostic marker or a therapeutic target of coronary artery disease.
    Yamashita Tomoya, Hirata Ken-ichi
    80th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2016, Japanese, the Japanese Circulation Society, 仙台, Gut microbiota was changed in CAD patients and could be a therapeutic target., Domestic conference
    Public symposium

  • Prevention of atherosclerosis via modulating intetinal function
    Yamashita Tomoya, Hirata Ken-ichi
    The 23rd Annual Meeting of the Japanese Vascular Biology and Medicine Organization, Dec. 2015, Japanese, The Japanese Vascular Biology and Medicine Organization, 神戸, Gut microbiota was changed in CAD patients and could be a therapeutic target., Domestic conference
    [Invited]
    Nominated symposium

  • Development of UVB-based phototherapy against atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, 笠原 和之, Fukunaga Atsushi, 山口智之, 江本 拓央, 淀井 景子, 松本 卓也, 中島 健爾, 北 智之, 武田 匡史, 溝口 泰司, 林 友鴻, 佐々木 義浩, 畠山 真弓, 田口 久美子, 鷲尾 健, 坂口志文, Nishigori Chikako, Hirata Ken-ichi
    The 23rd Annual Meeting of the Japanese Vascular Biology and Medicine Organization, Dec. 2015, Japanese, The Japanese Vascular Biology and Medicine Organization, 神戸, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., Domestic conference
    Oral presentation

  • CTLA-4 prevents atherosclerosis in mice
    松本 卓也, Sasaki Naoto, 江本 拓央, 溝口 泰司, 林 友鴻, 吉田 尚史, Yamashita Tomoya, Hirata Ken-ichi
    The 23rd Annual Meeting of the Japanese Vascular Biology and Medicine Organization, Dec. 2015, Japanese, The Japanese Vascular Biology and Medicine Organization, 神戸, CTLA-4 prevents atherosclerosis in mice, Domestic conference
    Oral presentation

  • A characteristic profile of gut microbiota in coronary artery disease
    江本 拓央, Yamashita Tomoya, Sasaki Naoto, 笠原 和之, 淀井 景子, 松本 卓也, 溝口 泰司, 林 友鴻, Hirata Ken-ichi
    The 23rd Annual Meeting of the Japanese Vascular Biology and Medicine Organization, Dec. 2015, Japanese, The Japanese Vascular Biology and Medicine Organization, 神戸, A characteristic change of gut microbiota was observed in CAD patients, Domestic conference
    Poster presentation

  • The characteristics of gut microbiota in coronary artery disease
    江本 拓央, Yamashita Tomoya, Sasaki Naoto, 笠原 和之, 淀井 景子, 松本 卓也, 溝口 泰司, 林 友鴻, Hirata Ken-ichi
    120th Kinki Regional Scientific Meeting of the Japanese Circulation Society, Nov. 2015, Japanese, Kinki Regional Office of the Japanese Circulation Society, 大阪, A characteristic change of gut microbiota was observed in CAD patients, Domestic conference
    Oral presentation

  • Investigation of the effect of UVB irradiation on atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Fukunaga Atsushi, 山口智之, 坂口志文, Nishigori Chikako, Hirata Ken-ichi
    The 43rd Annual Meeting of the Japan Society for Clinical Immunology, Oct. 2015, Japanese, The Japan Society for Clinical Immunology, 神戸, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., Domestic conference
    Poster presentation

  • A possible link of gut microbiota alteration in atherosclerotic cardiovascular diseases.
    Yamashita Tomoya, Hirata Ken-ichi
    4th International Congress on Lipid Metabolism & Atherosclerosis., Sep. 2015, English, Korean Socisty of Lipidology and Atherosclerosis, ソウル, 韓国, A characteristic change of gut microbiota was observed in CAD patients, International conference
    [Invited]
    Nominated symposium

  • A Characteristic Change of Gut Microbiota in Coronary Artery Disease
    江本 拓央, Yamashita Tomoya, Sasaki Naoto, 笠原 和之, 淀井 景子, 松本 卓也, 溝口 泰司, 林 友鴻, 宗 杏奈, Hirota Yushi, Ogawa Wataru, Hirata Ken-ichi
    The 47th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2015, Japanese, The Japan Atherosclerosis Society, 仙台, Coronary artery disease was associated with a change in the composition of gut microbiota., Domestic conference
    Poster presentation

  • The characteristics of gut microbiota in coronary artery disease
    江本 拓央, Yamashita Tomoya, Sasaki Naoto, 笠原 和之, 淀井 景子, 松本 卓也, 溝口 泰司, 林 友鴻, Hirata Ken-ichi
    19th Annual Meeting of Intestinal Microbiology, Jun. 2015, Japanese, Japan Bifidus Foundation, 東京, A characteristic change of gut microbiota was observed in CAD patients, Domestic conference
    Oral presentation

  • Regulatory T Cells and Tolerogenic Dendritic Cells are Critical Immunomodulators Linking the Skin and Intestinal Immune System to Atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, Japanese, the Japanese Circulation Society, 大阪, The skin and intestine could be new therapeutic targets for preventing atherosclerotic disease., Domestic conference
    [Invited]
    Nominated symposium

  • Proatherogenic Immune Responses are Regulated by Overexpression of a Coinhibitory Molecule CTLA-4 in Apolipoprotein E-deficient Mice
    Takuya Matsumoto, Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Keiko Yodoi, Takuo Emoto, Taiji Mizoguchi, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, English, the Japanese Circulation Society, 大阪, CTLA-4 regulates proatherogenic immune responses through cell intrinsic and extrinsic pathways and could be an attractive therapeutic target for atherosclerosis., Domestic conference
    Oral presentation

  • Intestinal Immunity and Gut Microbiota as Therapeutic Targets for Preventing Atherosclerotic Cardiovascular Diseases
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, English, the Japanese Circulation Society, 大阪, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Foxp3+ Regulatory T Cells Play a Protective Role in Angiotensin II-induced Aortic Aneurysm Formation in Mice
    Keiko Yodoi, Yamashita Tomoya, Sasaki Naoto, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuo Emoto, Takuya Matsumoto, Taiji Mizoguchi, Tomoyuki Kita, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, English, the Japanese Circulation Society, 大阪, We clarified the role of regulatory T cells in the development of aortic aneurysm., Domestic conference
    Oral presentation

  • Foxp3+ Regulatory T Cells and T Regulatory Type 1 Cells Cooperatively Inhibit the Development of Atherosclerosis in Mice
    Kazuyuki Kasahara, Sasaki Naoto, Yamashita Tomoya, Keiko Yodoi, Takuya Matsumoto, Takuo Emoto, Taiji Mizoguchi, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, English, the Japanese Circulation Society, 大阪, Foxp3+ Tregs and Tr1 cells would cooperatively inhibit atherosclerotic plaque formation in hypercholesterolemic mice., Domestic conference
    Oral presentation

  • A Characteristic Change of Gut Microbiota in Coronary Artery Disease
    Takuo Emoto, Yamashita Tomoya, Sasaki Naoto, Kazuyuki Kasahara, Keiko Yodoi, Takuya Matsumoto, Taiji Mizoguchi, Tomohiro Hayashi, Hirata Ken-ichi
    79th Annual Scientific Meeting of the Japanese Circulation Society, Apr. 2015, English, the Japanese Circulation Society, 大阪, Coronary artery disease was associated with a change in the composition of gut microbiota., Domestic conference
    Poster presentation

  • 肺扁平上皮癌術後に臨床経過から肺腫瘍源性塞栓性微小血管症が疑われ病理解剖を行った一例
    西原侑紀, Nakayama Kazuhiko, 絹谷洋人, 林友鴻, 新倉悠人, 元地由樹, Takaya Tomofumi, Yamashita Tomoya, 江本憲昭, Hirata Ken-ichi
    第207回日本内科学会近畿地方会, Mar. 2015, Japanese, 日本内科学会, 大阪, Domestic conference
    Oral presentation

  • Circulating intermediate CD14++CD16+ monocytes increase in patients with atrial fibrillation and reflect functional remodeling of left atrium
    Atsushi Suzuki, Fukuzawa Koji, Yamashita Tomoya, Yoshida Akihiro, Sasaki Naoto, Takuo Emoto, Asumi Takei, Ryudo Fujiwara, Tomoyuki Nakanishi, Soichiro Yamashita, Akinori Matsumoto, Hiroki Konishi, Hirotoshi Ichibori, Hirata Ken-ichi
    64th Annual Scientific Session, American College of Cardiology, Mar. 2015, English, American College of Cardiology, San Diego, USA, Background: Recent large clinical study demonstrated association of intermediate CD14++CD16+monocytes (IM) with cardiovascular events. We investigated the possible role of IM in pathophysiology of atrial fibrillation (AF). Methods: This case-control study included 30 AF patients (17 paroxysmal and 13 persistent AF patients) who were referred for catheter ablation, and 30 health, International conference
    Poster presentation

  • 高心拍出性ショックを伴う肺高血圧症を呈し急性期診断に苦慮した一例
    清水真央, Nakayama Kazuhiko, 絹谷洋人, 新倉悠人, 笠松朗, Takaya Tomofumi, Shinke Toshiro, Yamashita Tomoya, Hirata Ken-ichi, 江本憲昭, 伊阪大二
    第118回日本循環器学会近畿地方会, Nov. 2014, Japanese, 日本循環器学会, 大阪, Domestic conference
    Oral presentation

  • Prevention of atherosclerosis bia intervention togut bacterial flora and modulation of intestinal immunity
    Yamashita Tomoya, Hirata Ken-ichi
    The 35th Annual Meeting of Japan Society for the Study of Obesity, Oct. 2014, Japanese, Japan Society for the Study of Obesity, 宮崎, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • 著明な肺高血圧を伴う先天性右肺動脈欠損症に対し肺血管拡張薬導入を行った1例
    鈴木 雅貴, Nakayama Kazuhiko, 絹谷 洋人, 新倉 悠人, 笠原 洋一郎, Shinke Toshiro, Takaya Tomofumi, Yamashita Tomoya, 江本 憲昭, Hirata Ken-ichi
    The 21thJapanese Association of Cardiovascular Interventionand Therapeutics, Oct. 2014, Japanese, Japanese Association of Cardiovascular Interventionand Therapeutics, 大阪, Domestic conference
    Oral presentation

  • 著明な肺高血圧を伴う先天性肺動脈欠損症に対し肺血管拡張薬導入を行った1例
    鈴木雅貴, Nakayama Kazuhiko, 絹谷洋人, 新倉悠人, 笠原洋一郎, Shinke Toshiro, Takaya Tomofumi, Yamashita Tomoya, 江本憲昭, Hirata Ken-ichi
    第205回日本内科学会近畿地方会, Sep. 2014, Japanese, 日本内科学会, 大阪, Domestic conference
    Oral presentation

  • Gut bacterial flora and atherosclerosis
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    The 46th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2014, Japanese, The Japan Atherosclerosis Society, 東京, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    Public symposium

  • Prevention of atherosclerosis bia intervention togut bacterial flora and modulation of intestinal immunity
    Yamashita Tomoya, Hirata Ken-ichi
    The 35th Annual Meeting of Japan Society of Circulation Control in Medicine, Jul. 2014, Japanese, The Japan Society of Circulation Control in Medicine, 福岡, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Regulatory T cells and CD4+CD28null T cells in coronary artery disease
    Takuo Emoto, Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Keiko Yodoi, Yoshihiro Sasaki, Takuya Matsumoto, Taiji Mizoguchi, Hirata Ken-ichi
    The 46th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2014, Japanese, The Japan Atherosclerosis Society, 東京, We clarified the role of regulatory T cells in human atherosclerotic disease., Domestic conference
    Poster presentation

  • Gut microbiota modulates coronary atherogenesis
    Takuo Emoto, Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Keiko Yodoi, Yoshihiro Sasaki, Takuya Matsumoto, Taiji Mizoguchi, Hirata Ken-ichi
    The 46th Annual Scientific Meeting of the Japan Atherosclerosis Society, Jul. 2014, Japanese, The Japan Atherosclerosis Society, 東京, A change of gut microbiota in coronary artery disease, Domestic conference
    Poster presentation

  • Glenn手術既往のある心室品拍患者に対して、心外膜にICDリードを留置した1例
    小西弘樹, Fukuzawa Koji, Yoshida Akihiro, Matsumoto Kensuke, 藤原竜童, 鈴木敦, 中西智之, 山下宗一郎, 松本晃典, 市堀博俊, Yamashita Tomoya, Takaya Tomofumi, Hirata Ken-ichi, Inoue Takeshi, Okita Yutaka
    第117回日本循環器学会近畿地方会, Jul. 2014, Japanese, 日本循環器学会近畿支部, 大阪, Domestic conference
    Oral presentation

  • Prevention of atherosclerosis bia intervention to intestine
    Yamashita Tomoya, Hirata Ken-ichi
    The 56th Annual Meeting of Japan Geriatrics Society, Jun. 2014, Japanese, The Japan Geriastrics Society, 福岡, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Particle Therapy Using Carbon Ions or Protons for Chondrosarcomas:a Single-Institution Retrospective Analysis
    Y Demizu, M Mima, D Jin, N Hasimoto, M Takagi, F Nagano, K Katsui, K Terashima, O Fujii, T Okimoto, Yamashita Tomoya, Y Toyomasu, Y Niwa, Sasaki Ryohei, M Murakami, Y Hishikawa, M Abe, N Fuwa
    The 53th Annual Conference of the Particle Therapy Co-Operative Group, Jun. 2014, English, PTCOG 53 Hosting/Organizing Committee, Shanghai, International conference
    Oral presentation

  • The effector/ regulatory T cell ratio is reduced in coronary artery disease
    Takuo Emoto, Sasaki Naoto, Taiji Mizoguchi, Takuya Matsumoto, Keiko Yodoi, Yoshihiro Sasaki, Kazuyuki Kasahara, Yamashita Tomoya, Hirata Ken-ichi
    78th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2014, English, the Japanese Circulation Society, 東京, We clarified the role of regulatory T cells in human atherosclerotic disease., Domestic conference
    Poster presentation

  • Regulatory T Cells Play a Protective Role in Angiotensin II-Induced Aortic Aneurysm Formation
    Keiko Yodoi, Yamashita Tomoya, Sasaki Naoto, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuo Emoto, Takuya Matsumoto, Taiji Mizoguchi, Hirata Ken-ichi
    78th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2014, Japanese, the Japanese Circulation Society, 東京, We clarified the role of regulatory T cells in the development of aortic aneurysm., Domestic conference
    Oral presentation

  • Regulation of Pathogenic Inflammatory Responses via Modulating Skin Immune System for Prevention of Atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    78th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2014, English, the Japanese Circulation Society, 東京, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., Domestic conference
    Oral presentation

  • Intestine and gut bacterial flora in atherogenesis.
    Yamashita Tomoya, Hirata Ken-ichi
    78th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2014, English, the Japanese Circulation Society, 東京, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Anti-CD3 antibody and interleukin-2 complex combination therapy inhibits atherosclerosis development by dramatically augmenting a regulatory immune response
    Kazuyuki Kasahara, Sasaki Naoto, Yamashita Tomoya, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    78th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2014, English, the Japanese Circulation Society, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., Domestic conference
    Poster presentation

  • Development of Novel Strategies for Preventing Atherosclerosis through Modulation of Immune System
    Sasaki Naoto, Yamashita Tomoya, Hirata Ken-ichi
    The 43rd meeting of Japanese Society for Circulation Research, Feb. 2014, Japanese, Japanese Society for Circulation Research, 神戸, Enhancement of an endogenous regulatory immune response could be a novel therapeutic approach against atherosclerotic disease., Domestic conference
    [Invited]
    Nominated symposium

  • Anti-CD3 antibody and interleukin-2 complex combination therapy inhibits atherosclerosis development by dramatically augmenting a regulatory immune response
    Kazuyuki Kasahara, Sasaki Naoto, Yamashita Tomoya, Yoshihiro Sasaki, Keiko Yodoi, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    The 43rd meeting of Japanese Society for Circulation Research, Feb. 2014, Japanese, Japanese Society for Circulation Research, 神戸, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., Domestic conference
    Poster presentation

  • Regulatory T Cells Play a Protective Role in Angiotensin II-Induced Aortic Aneurysm Formation
    Keiko Yodoi, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuo Emoto, Takuya Matsumoto, Taiji Mizoguchi, Hirata Ken-ichi
    The 43rd meeting of Japanese Society for Circulation Research, Feb. 2014, Japanese, Japanese Society for Circulation Research, 神戸, We clarified the role of regulatory T cells in the development of aortic aneurysm., Domestic conference
    Poster presentation

  • A novel strategy against atherosclerosis targeting regulatory T cells
    Sasaki Naoto, Yamashita Tomoya, Hirata Ken-ichi
    第34回心筋生検研究会, Nov. 2013, Japanese, 心筋生検研究会, 松本, Enhancement of an endogenous regulatory immune response could be a novel therapeutic approach against atherosclerotic disease., Domestic conference
    [Invited]
    Invited oral presentation

  • In vivo expansion of regulatory T cells attenuates aortic aneurysm formation in angiotensin II- infused apolipoprotein E-deficient mice
    Keiko Yodoi, Sasaki Naoto, Taiji Mizoguchi, Takuya Matsumoto, Takuo Emoto, Yoshihiro Sasaki, Kazuyuki Kasahara, Tomoyuki Kita, Yamashita Tomoya, Hirata Ken-ichi
    The 86th AHA Scientific Sessions, Nov. 2013, English, American heart association, Dallas, USA, We clarified the role of regulatory T cells in the development of aortic aneurysm., International conference
    Oral presentation

  • A novel combination therapy with anti-CD3 antibody and IL-2 complexes against atherosclerosis targeting effector T cells and regulatory T cells
    Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    The 86th AHA Scientific Sessions, Nov. 2013, English, American heart association, Dallas, USA, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., International conference
    Poster presentation

  • Activation of skin dendritic cells controls atherogensis in mice
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    The 86th AHA Scientific Sessions, Nov. 2013, English, American heart association, Dallas, USA, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., International conference
    Poster presentation

  • Activation of regulatory T cells by ultraviolet irradiation controls atherogenesis in mice
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Kenji Nakajima, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Masafumi Takeda, Hirata Ken-ichi
    The 85th AHA Scientific Sessions, Nov. 2013, English, American heart association, ロサンゼルス(アメリカ合衆国), Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., International conference
    Poster presentation

  • Prevention of atherosclerosis bia intervention to intestine
    Yamashita Tomoya, Hirata Ken-ichi
    23rd Annual Meeting of Japan Pathphysiology Society, Aug. 2013, Japanese, The Japan Pathphysiology Society, 東京, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Prevention of atherosclerosis bia intervention to intestine
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    45th Annual Society Meeting of the Japan Atherosclerosis Society, Jul. 2013, Japanese, The Japan Atherosclerosis Society, 東京, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • The effects in vivo expansion of regulatory T cells on abdominal aortic aneurysm in the angiotensin II-induced murine model
    Keiko Yodoi, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    45th Annual Society Meeting of the Japan Atherosclerosis Society, Jul. 2013, Japanese, The Japan Atherosclerosis Society, 東京, We clarified the role of regulatory T cells in the development of aortic aneurysm., Domestic conference
    Poster presentation

  • The balance between regulatory T cells and effector T cells is important for the control of atherosclerosis
    Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    45th Annual Society Meeting of the Japan Atherosclerosis Society, Jul. 2013, Japanese, The Japan Atherosclerosis Society, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., Domestic conference
    Poster presentation

  • Regression of atherosclerosis with anti-CD3 antibody via modulating the ratio of effector and regulatory T cells in mice
    Yoshihiro Sasaki, Sasaki Naoto, Yamashita Tomoya, Tomoyuki Kita, Kazuyuki Kasahara, Keiko Yodoi, Hirata Ken-ichi
    45th Annual Society Meeting of the Japan Atherosclerosis Society, Jul. 2013, Japanese, The Japan Atherosclerosis Society, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., Domestic conference
    Poster presentation

  • Activation of skin dendritic cells controls atherogensis in mice
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    45th Annual Society Meeting of the Japan Atherosclerosis Society, Jul. 2013, Japanese, The Japan Atherosclerosis Society, 東京, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., Domestic conference
    Poster presentation

  • Novel therapeutic strategies for preventing atherosclerosis via modulating intestinal immunity and intervention to gut microflora.
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    17th The Annual Meeting of Intestinal Microbiology, Jun. 2013, Japanese, The Japan Bifidus Foundation, 東京, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • Novel therapeutic strategies for preventing atherosclerosis via modulating intestinal immunity
    Yamashita Tomoya
    13rd Japan Society of Anti-Aging Medicine, Jun. 2013, Japanese, Japan Society of Anti-Aging Medicine, 横浜, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, Domestic conference
    [Invited]
    Nominated symposium

  • 持続血糖モニタリングにて判明した胃切除後血糖変動が誘因の一つと考えられた急性冠症候群の一例
    黒田優, Shinke Toshiro, Sakaguchi Kazuhiko, Yamashita Tomoya, Otake Hiromasa, Hirota Yushi, 西尾亮, Hirata Ken-ichi
    Scientific session of Japanese Society of Internal Medicine, Apr. 2013, Japanese, Japanese Society of Internal Medicine, 東京, Domestic conference
    Oral presentation

  • ステロイド治療が著効したリンパ球浸潤を伴わない心GVHD
    川野 宏樹, 江本 拓央, 森 健茂, Tanaka Hidekazu, Yamashita Tomoya, Hirata Ken-ichi, 若橋 香奈子, 川野 裕子, 定 明子, 皆川 健太郎, 松井 利充, Katayama Yoshio
    The 35th Annual Meeting of the Japan Society for Hematopoietic Cell Transplantation, Mar. 2013, Japanese, The Japan Society for Hematopoietic Cell Transplantation, 金沢, Domestic conference
    Poster presentation

  • In vivo expansion of regulatory T cells attenuates aortic aneurysm formation in angiotensin II- infused apolipoprotein E-deficient mice
    Keiko Yodoi, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Kazuyuki Kasahara, Yoshihiro Sasaki, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    The 77th annual scientific meeting of the Japanese Circulation Society., Mar. 2013, English, Th Japanese Circulating Socirty, 横浜, We clarified the role of regulatory T cells in the development of aortic aneurysm., Domestic conference
    Poster presentation

  • Intestine and skin could be novel therapeutic targets for preventing cardiovascular diseases.
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    The 77th annual scientific meeting of the Japanese Circulation Society., Mar. 2013, Japanese, Th Japanese Circulating Socirty, 横浜, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing cardiovascular diseases We for the first time proposed that the gut and skin immune systems could be thera, Domestic conference
    Public symposium

  • A novel mouse model to deplete regulatory T cells uncovers their role in atherogenesis under hypercholesterolemia
    Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    The 77th annual scientific meeting of the Japanese Circulation Society., Mar. 2013, English, Th Japanese Circulating Socirty, 横浜, We clarified the role of regulatory T cells in the development of atherosclerosis., Domestic conference
    Poster presentation

  • A novel combination therapy with anti-CD3 antibody and IL-2 complexes against atherosclerosis targeting effector T cells and regulatory T cells
    Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Takuo Emoto, Takuya Matsumoto, Hirata Ken-ichi
    The 77th annual scientific meeting of the Japanese Circulation Society., Mar. 2013, English, Th Japanese Circulating Socirty, 横浜, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., Domestic conference
    Oral presentation

  • Development of novel antii-atherogenic therapy through modulation of intestinal immunity
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    The 44th Annual Meeting of Japanese AtherosclerosisSociety, Jul. 2012, Japanese, Japan Atherosclerosis Society, 福岡, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing cardiovascular diseases We for the first time proposed that the gut and skin immune systems could be thera, Domestic conference
    Public symposium

  • Development of novel antii-atherogenic therapy through modulation of intestinal and skin immunity
    Yamashita Tomoya
    Symposium of Japanese Association for Food Science, Jun. 2012, Japanese, Japanese Association for Food Science, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing cardiovascular diseases We for the first time proposed that the gut and skin immune systems could be thera, Domestic conference
    [Invited]
    Nominated symposium

  • The Expansion of Regulatory T Cells with IL-2/IL-2mAb Complexes Reduces the Development of Atherosclerosis
    Kazuyuki Kasahara, Yamashita Tomoya, Sasaki Naoto, Tomoyuki Kita, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    第76回日本循環器学会総会・学術集会, Mar. 2012, English, 日本循環器学会, 福岡, Domestic conference
    Poster presentation

  • Regulation of Inflammation via Modulating Intestinal Immunity for Prevention of Atherosclerotic Cardiovascular Diseases
    Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    第76回日本循環器学会総会・学術集会, Mar. 2012, Japanese, 日本循環器学会, 福岡, Domestic conference
    Oral presentation

  • Immunosuppressive Agent Anti-CD3 Antibody But Not Everolimus Regresses Established Atherosclerosis Althogh Both Dramatically Reduce Effector T Cells in Mice
    Tomoyuki Kita, Yamashita Tomoya, Sasaki Naoto, Kazuyuki Kasahara, Yoshihiro Sasaki, Keiko Yodoi, Hirata Ken-ichi
    第76回日本循環器学会総会・学術集会, Mar. 2012, English, 日本循環器学会, 福岡, Domestic conference
    Oral presentation

  • A novel ultraviolet-based phototherapy against atherosclerosis targeting regulatory T cells and skin dendritic cells
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Kenji Nakajima, Tomoyuki Kita, Masafumi Takeda, Hirata Ken-ichi
    第76回日本循環器学会総会・学術集会, Mar. 2012, English, 日本循環器学会, 福岡, Domestic conference
    [Invited]
    Invited oral presentation

  • A novel ultraviolet-based phototherapy against atherosclerosis targeting regulatory T cells and skin dendritic cells
    Sasaki Naoto, Yamashita Tomoya, Kazuyuki Kasahara, Kenji Nakajima, Tomoyuki Kita, Masafumi Takeda, Hirata Ken-ichi
    The XVI International Symposium on Atherosclerosis (ISA2012), Mar. 2012, English, 国際動脈硬化学会, シドニー, オーストラリア, International conference
    Oral presentation

  • Sunshine May Protect Ourself against Atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, Kenji Nakajima, Tomoyuki Kita, Masafumi Takeda, Kazuyuki Kasahara, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Aug. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Intraperitoneal Injection of an Active form Vitamin D3 Decreases Atherosclerosis in Mice via Inducing Tolerogenic Dendritic Cells
    Masafumi Takeda, Yamashita Tomoya, Tomoyuki Kita, Kenji Nakajima, Kazuyuki Kasahara, Sasaki Naoto, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Aug. 2011, Japanese, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • A Novel Atherosclerosis Regression Mouse Model for Investigating Its Underlying Mechanism
    Kenji Nakajima, Yamashita Tomoya, Tomoyuki Kita, Masafumi Takeda, Sasaki Naoto, Kazuyuki Kasahara, Masakazu Shinohara, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Aug. 2011, Japanese, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Administration of Vasoactive Intestinal Peptide, an Immunoregulatory Neuropeptide, Reduces Atherosclerosis in Mice through Inducing Regulatory T Cells
    Kazuyuki Kasahara, Yamashita Tomoya, Masafumi Takeda, Kenji Nakajima, Tomoyuki Kita, Sasaki Naoto, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Aug. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Administration of Anti-CD3 Antibody Induces Regression of Established Atherosclerosis through Decreasing Effector T Cells But Not Increasing Regulatory T Cells
    Tomoyuki Kita, Yamashita Tomoya, Masafumi Takeda, Kenji Nakajima, Kazuyuki Kasahara, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Aug. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Ultraviolet irradiation to the skin prevents atherosclerosis through induction of regulatory T cells
    Sasaki Naoto, Yamashita Tomoya, Hirata Ken-ichi
    第43回日本動脈硬化学会, Jul. 2011, Japanese, 日本動脈硬化学会, 札幌, Domestic conference
    Poster presentation

  • Oral Administration of an Active Form of Vitamin D3 (Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions.
    武田匡史, Yamashita Tomoya, Sasaki Naoto, Hirata Ken-ichi
    第43回日本動脈硬化学会, Jul. 2011, Japanese, 日本動脈硬化学会, 札幌, Domestic conference
    [Invited]
    Invited oral presentation

  • Anti-atherogenic immune therapy via modulation of the intestinal immune system. -The intestines as new therapeutic targets for preventing atherosclerosis-
    Yamashita Tomoya, 武田匡史, 中島健爾, Sasaki Naoto, Hirata Ken-ichi
    第43回日本動脈硬化学会, Jul. 2011, Japanese, 日本動脈硬化学会, 札幌, Domestic conference
    Oral presentation

  • Oral administration of an active form vitamin D3 (calcitriol) decreases atherosclerosis in mice via inducing regulatory T cells and immature dendritic cells with tolerogenic functions.
    Yamashita Tomoya, Masafumi Takeda, Sasaki Naoto, Kenji Nakajima, Tomoyuki Kita, Masakazu Shinohara, Ishida Tatsuro, Hirata Ken-ichi
    Arteriosclerosis, Thrombosis,and Vascular Biology 2011, Apr. 2011, English, American Heart Association, シカゴ, 米国, International conference
    [Invited]
    Invited oral presentation

  • Suppression of effector T cells but not increase of regulatory T cells via administration of anti-CD3 antibody induces the regression of established atherosclerosis in mice
    北 智之, Yamashita Tomoya, 武田 匡史, 中島 健爾, 笠原 和之, Hirata Ken-ichi
    第75回日本循環器学会総会・学術集会, Mar. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Sunshine may protect ourself against atherosclerosis
    Sasaki Naoto, Yamashita Tomoya, 中島 健爾, 北 智之, 武田 匡史, 笠原 和之, Hirata Ken-ichi
    第75回日本循環器学会総会, Mar. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Intraperitoneal injection of an active form Vitamin D3 decreases atherosclerosis in mice via inducing tolerogenic dendritic cells.
    Masafumi Takeda, Yamashita Tomoya, Tomoyuki Kita, Kenji Nakajima, Sasaki Naoto, Kazuyuki Kasahara, Hirata Ken-ichi
    第75回日本循環器学会総会, Mar. 2011, Japanese, 日本循環器病学会, 横浜, Domestic conference
    Poster presentation

  • A novel atherosclerosis regression mouse model for investigating its underlying mechanism
    Kenji Nakajima, Yamashita Tomoya, Tomoyuki Kita, Masafumi Takeda, Sasaki Naoto, Kazuyuki Kasahara, Masakazu Shinohara, Hirata Ken-ichi
    第75回日本循環器学会総会, Mar. 2011, Japanese, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • Administration of Vasoactive Intestinal Peptide, an Immunoregulatory Neuropeptide, Reduces Atherosclerosis in Mice through Inducing Regulatory T Cells
    笠原 和之, Yamashita Tomoya, 武田 匡史, 中島 健爾, 北 智之, Sasaki Naoto, Hirata Ken-ichi
    第75回日本循環器学会総会, Mar. 2011, English, 日本循環器学会, 横浜, Domestic conference
    Poster presentation

  • 長期に経過を観察し、ステロイド中止により再燃した慢性心筋炎の一例
    永松裕一, Yamashita Tomoya, 漁 恵子, 松田康章, Ishida Tatsuro, Yoshida Akihiro, 志手淳也, 川合宏哉, Hirata Ken-ichi
    第110回日本循環器学会近畿地方会, Nov. 2010, Japanese, 日本循環器学会, 京都, Domestic conference
    Oral presentation

  • Orally Administered Eicosapentaenoic Acid Induces Rapid Regression of Atherosclerosis via Modulating the Phenotype of Dendritic Cells in LDL Receptor-deficient Mice.
    Kenji Nakajima, Yamashita Tomoya, Masafumi Takeda, Sasaki Naoto, Tomoyuki Kita, Masakazu Shinohara, Hirata Ken-ichi
    AHA Scientific Sessions 2010, Nov. 2010, English, アメリカ心臓協会, シカゴ, アメリカ合衆国, International conference
    Poster presentation

  • Effector T Cell Suppression Using Anti- CD3 Antibody Induces The Regression of Established Atherosclerosis in Mice
    北 智之, Yamashita Tomoya, 武田 匡史, 中島 健爾, Hirata Ken-ichi
    AHA Scientific Sessions 2010, Nov. 2010, English, アメリカ心臓協会, シカゴ, アメリカ合衆国, International conference
    Oral presentation

  • Anti-inflammatory and immune modulation therapy against atherosclerosis
    Yamashita Tomoya, Sasaki Naoto, 武田 匡史, Hirata Ken-ichi
    第42回日本動脈硬化学会総会・学術集会, Jul. 2010, Japanese, 日本動脈硬化学会, 岐阜, Domestic conference
    Oral presentation

  • Oral Anti-CD3 Antibody Treatment Induces Regulatory T Cells and Inhibits the Development of Atherosclerosis in Mice
    Sasaki Naoto, Yamashita Tomoya, 武田 匡史, 篠原 正和, 中島 健爾, 多和 秀人, 臼井 崇, Hirata Ken-ichi
    第42回日本動脈硬化学会総会・学術集会, Jul. 2010, Japanese, 日本動脈硬化学会, 岐阜, Domestic conference
    Oral presentation

  • MRIが診断と治療方針決定に有効であったEffusive constrictive pericarditisの1症例
    永野 雄一朗, Yamashita Tomoya, 金子 明弘, 名越 良治, Toh Ryuji, Yoshida Akihiro, 川合 宏哉, Hirata Ken-ichi, 南 一司, Okita Yutaka
    第191回日本内科学会近畿地方会学術集会, Jun. 2010, Japanese, 日本内科学会近畿地方会, 京都, Domestic conference
    Oral presentation

  • BH4/BH2 ratio as a novel marker of endothelial function
    Yamashita Tomoya, 武田 匡史, Hirata Ken-ichi
    第107回日本内科学会講演会, Apr. 2010, Japanese, 日本内科学会, 東京, Domestic conference
    Poster presentation

  • Orally Administered Eicosapentaenoic Acid Induce Rapid Regression of Atherosclerosis via Modulating the Phenotype of Dendritic Cells in LDL Receptor-deficient Mice
    Yamashita Tomoya, Sasaki Naoto, Shinohara Masakazu, Hirata Kenichi
    日本循環器学会 第74回総会・学術集会, Mar. 2010, English, 日本循環器学会, 京都, Domestic conference
    Oral presentation

  • Oral administration of an active form Vitamin D3 (Calcitriol) decreases atherosclerosis in mice via modulating immune cell phenotypes and functions.
    Yamashita Tomoya, Shinohara Masakazu, Hirata Kenichi
    日本循環器学会 第74回学術集会, Mar. 2010, English, 日本循環器学会, 京都, Domestic conference
    Poster presentation

  • Oral administration of an active form Vitamin D3 (Calcitriol) decreases atherosclerosis in mice via modulating immune cell phenotypes and functions.
    Yamashita Tomoya, Sasaki Naoto, Shinohara Masakazu, Hirata Kenichi
    AHA 2009, Nov. 2009, English, American Heart Association, フロリダ(オーランド), アメリカ, International conference
    Poster presentation

  • 診断に苦慮し、心筋生検像をもとにステロイド治療を行った心筋炎の1例
    Yamashita Tomoya, Toh Ryuji, Kawai Hiroya, Shite Junya, Hirata Kenichi
    日本内科学会 第189回近畿地方会, Sep. 2009, Japanese, 日本内科学会, 大阪, Domestic conference
    Oral presentation

  • Effects of UVB exposure on atherosclerotic lesion formation in mice.
    Sasaki Naoto, Yamashita Tomoya, Shinohara Masakazu, Fukunaga Atsushi, Nishigori Chikako, Hirata Kenichi
    第31回日本光医学・光生物学会, Jul. 2009, Japanese, 日本光医学・光生物学会, 大阪, Domestic conference
    Oral presentation

  • Plasma tetrahydrobiopterin / dihydrobiopterin : A possible marker of endothelial dysfunction
    Yamashita Tomoya, Shinohara Masakazu, Sasaki Naoto, Kobayashi Seimi, Toh Ryuji, Hirata Kenichi, Kawashima Seinosuke
    第8回NO学会, May 2009, Japanese, 日本NO学会, 仙台, Domestic conference
    Poster presentation

  • Improved Metabolic Syndrome and Atherosclerosis by oral Eicosapentaenoic acid (EPA) treatment in LDLR-deficient mice.
    Shinohara Masakazu, Yamashita Tomoya, Sasaki Naoto, Hirata Kenichi
    第73回日本循環器学会 総会, Mar. 2009, English, 日本循環器学会, 大阪, Domestic conference
    Poster presentation

  • CPAより蘇生に成功し、ICD植込みを行った冠攣縮性狭心症の一症例
    Yamashita Tomoya, Ishida Tatsuro, Yoshida Akihiro, Shite Junya, Kawai Hiroya, Hirata Kenichi
    日本循環器学会 第106回近畿地方会, Nov. 2008, Japanese, 日本循環器学会, 神戸, Domestic conference
    Oral presentation

  • Plasma pteridine level as a biomarker of cardiovascular diseases
    Shinohara Masakazu, Yamashita Tomoya, Sasaki Naoto, Toh Ryuji, Kobayashi Seimi, Kawashima Seinosuke, Hirata Kenichi
    第72回日本循環器学会総会・学術総会, Mar. 2008, English, 日本循環器学会, 福岡, Domestic conference
    Poster presentation

  • Oral Anti-CD3 Antibody Treatment Induces CD4+LAP+ Regulatory T Cells and Ameliorates the Development of Atherosclerosis in Mice
    Sasaki Naoto, Yamashita Tomoya, Shinohara Masakazu, Toh Ryuji, Kobayashi Seimi, Hirata Kenichi
    第72回日本循環器学会総会・学術総会, Mar. 2008, English, 日本循環器学会, 福岡, Domestic conference
    Poster presentation

  • Atherosclerotic Plaque Imaging using Phase-Contrast X-ray Computed Tomography- Seeking for Clinical Application -
    Shinohara Masakazu, Yamashita Tomoya, Sasaki Naoto, Toh Ryuji, Yokoyama Mitsuhiro, Hirata Kenichi
    第72回日本循環器学会総会・学術総会, Mar. 2008, English, 日本循環器学会, 福岡, Domestic conference
    Oral presentation

  • Oral Anti-CD3 Antibody Treatment Induces CD4+LAP+ Regulatory T Cells and Ameliorates the Development of Atherosclerosis in Mice
    Sasaki Naoto, Yamashita Tomoya, Shinohara Masakazu, Toh Ryuji, Kobayashi Seimi, Hirata Kenichi
    第79回AmericanHeartAssociationScientificSession, Nov. 2007, English, The American Heart Association, Orland, アメリカ, International conference
    Oral presentation

  • Myofilament Disarray in a Failing Heart of the MLP-deficient Mouse: Evidence from X-Ray Diffraction Study Using Synchrotron Radiation
    Toh Ryuji, Shinohara Masakazu, Sasaki Naoto, Yamashita Tomoya, Yokoyama Mitsuhiro
    第11回日本心不全学会学術集会, Sep. 2007, Japanese, 日本心不全学会, 東京, Domestic conference
    Poster presentation

  • 肺動脈血栓内膜摘除術が奏功した若年発症の慢性肺動脈血栓塞栓症の一例
    Yamashita Tomoya, Yoshida Akihiro, Emoto Noriaki, Kawai Hiroya, Shite Junya, Hirata Kenichi, Yokoyama Mitsuhiro, Matsumori Masamichi, Okada Kenji, Okita Yutaka
    第103回日本日本循環器学会近畿地方会, Jun. 2007, Japanese, 日本循環器学会, 大阪, Domestic conference
    Oral presentation

  • Plasma biopterin levels as a biomarker of endothlial dysfunction
    YAMASHITA TOMOYA, Shiraki Rio, TOH RYUJI, HIRATA KENICHI, Yokoyama Mitsuhiro
    第71回日本循環器学会総会・学術集会, Mar. 2007, English, 日本循環器学会, 神戸, Domestic conference
    Oral presentation

  • Myofilament Disarray in a Heart of Murine Dilated Cardiomyopathy Model: Evidense from X-ray Diffraction Study Using Synchrotron Radiation
    TOH RYUJI, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第71回日本循環器学会総会・学術集会, Mar. 2007, English, 日本循環器学会, 神戸, Domestic conference
    Oral presentation

  • How to Regulate the Inflammation in Atherogenesis-Novel Vaccine Strategies for Prevention of Atheroscletosis
    YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第71回日本循環器学会総会・学術集会, Mar. 2007, English, 日本循環器学会, 神戸, Domestic conference
    [Invited]
    Invited oral presentation

  • Augmentation of Vascular Remodeling by Uncoupled eNOS in a Mouse Model of Diabetes Mellitus
    Shiraki Rio, TOH RYUJI, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第71回日本循環器学会総会・学術集会, Mar. 2007, English, 日本循環器学会, 神戸, Domestic conference
    Oral presentation

  • An X-ray Diffraction Study on Mouse Cardiac Cross-Brigde Dynamics in vivo: Effects of Changing Heart Rate
    TOH RYUJI, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第71回日本循環器学会総会・学術集会, Mar. 2007, English, 日本循環器学会, 神戸, Domestic conference
    Oral presentation

  • Augmentation of Vascular Remodeling due to Uncoupled eNOS in Diabetes
    Kawashima Seinosuke, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    アメリカ心臓病学会(AHA), Nov. 2006, English, American Heart Association, シカゴ, International conference
    Poster presentation

  • 高血糖下ではeNOSアンカップリングにより血管リモデリングは悪化する
    Kawashima Seinosuke, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第47回日本脈管学会, Oct. 2006, Japanese, 日本脈管学会, 神戸, Domestic conference
    Oral presentation

  • 血管内皮機能の新たな血中マーカーとしての血中バイオプテリン濃度
    YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    第47回日本脈管学会, Oct. 2006, Japanese, 日本脈管学会, 神戸, Domestic conference
    Oral presentation

  • The possible role of oxidative stress caused by uncoupled eNOS in left ventricular remodeling after myocardial infarction in rat
    Kawashima Seinosuke, TOH RYUJI, YAMASHITA TOMOYA, Yokoyama Mitsuhiro
    ヨーロッパ心臓病学会(ESC), Sep. 2006, English, ヨーロッパ心臓病学会(ESC), バルセロナ, International conference
    Poster presentation

  • Mouse Cardiac Cross-Bridge Function Assessed in vivo by An X-ray Diffraction: Effects of Adrenergic beta-stimulation
    Ryuji Toh, Naoto Yagi, Masakazu Shinohara, Tomofumi Takaya, YAMASHITA,Tomoya, Naoto Sasaki, Tomoya Masano, KAWASHIMA, Seinosuke, YOKOYAMA, Mitsuhiro
    第70回日本循環器学会総会・学術集会, Mar. 2006, English, 日本循環器学会, 名古屋, Domestic conference
    Oral presentation

  • Xenogenic Smooth Muscle Cell Immunization Reduces Neointimal Formation in Balloon-Injured Rabbit Carotid Arteries
    Masakazu Shinohara, KAWASHIMA, Seinosuke, YAMASHITA,Tomoya, Tomofumi Takaya, Ryuji Toh, ISHIDA, Tatsuro, Tomomi Ueyama, INOUE,Nobutaka, Ken-ichi Hirata, YOKOYAMA, Mitsuhiro
    第78回American Heart Association Scientific Session, Nov. 2005, English, American Heart Association, ダラス, International conference
    Oral presentation

  • An X-ray Diffraction Study on Mouse Cardiac Cross-Bridge Function in Vivo: Effects of Adrenergic Beta-stimulation
    Ryuji Toh, Naoto Yagi, Masakazu Shinohara, Tomofumi Takaya, Shigeru Masuda, YAMASHITA,Tomoya, KAWASHIMA, Seinosuke, YOKOYAMA, Mitsuhiro
    第78回American Heart Association Scientific Session, Nov. 2005, English, American Heart Association, ダラス, International conference
    Poster presentation

  • An X-ray Diffraction Study on Mouse Cardiac Cross-Bridge Function in vivo: Effects of Adrenergic beta-stimulation
    Ryuji Toh, Naoto Yagi, Masakazu Shinohara, Tomofumi Takaya, YAMASHITA,Tomoya, KAWASHIMA, Seinosuke, YOKOYAMA, Mitsuhiro
    日本心不全学会学術集会(第9回), Oct. 2005, Japanese, 日本心不全学会, 下関, Domestic conference
    Oral presentation

  • Angiotensin II Type 1 Receptor Blocker, Telmisartan Suppresses Superoxide Production and Atherosclerotic Lesion Formation in Apolipoprotein E-deficient Mice
    Tomofumi Takaya, KAWASHIMA, Seinosuke, YAMASHITA,Tomoya, Masakazu Shinohara, INOUE,Nobutaka, Ken-ichi Hirata, YOKOYAMA, Mitsuhiro
    International Symposium on Atherosclerosis 2005, Jun. 2005, English, ローマ, International conference
    Poster presentation

  • In Vivo Evaluation of X-ray Diffraction from the Left Ventricular Wall of Mouse Hearts
    Ryuji Toh, Naoto Yagi, KAWASHIMA, Seinosuke, YAMASHITA,Tomoya, Masakazu Shinohara, Tomofumi Takaya, Shigeru Masuda, YOKOYAMA, Mitsuhiro
    American College of Cardiology Annual Scientific Session 2005, Mar. 2005, English, American College of Cardiology, オーランド, International conference
    Poster presentation

  • Overexpression of endothelial nitric oxide synthase accelerates vascular remodeling in apoE-deficient mice
    篠原 正和, KAWASHIMA, Seinosuke, 高谷 具史, YAMASHITA,Tomoya, INOUE,Nobutaka, HIRATA, Kenichi, YOKOYAMA, Mitsuhiro
    第68回日本循環器学会総会・学術集会, Mar. 2004, English, 日本循環器学会, 東京, Domestic conference
    Poster presentation

  • 循環器疾患における放射光微小血管造影の応用
    篠原 正和, YAMASHITA,Tomoya, 高谷 具史, KAWASHIMA, Seinosuke, YOKOYAMA, Mitsuhiro
    第9回放射光医学研究会, Jan. 2004, Japanese, 放射光医学研究会, 東京, Domestic conference
    Oral presentation

  • Xenogenic Smooth Muscle Cell Immunization as a Vaccine Reduces Neointimal Formation in Balloon-Injured Rabbit Carotid Arteries
    Masakazu Shinohara, KAWASHIMA, Seinosuke, Tomofumi Takaya, YAMASHITA,Tomoya, INOUE,Nobutaka, Ken-ichi Hirata, YOKOYAMA, Mitsuhiro
    第13回国際動脈硬化学会サテライトシンポジウム, Oct. 2003, English, 日本動脈硬化学会, 神戸, International conference
    Oral presentation

  • 異種血管平滑筋細胞を用いた免疫誘導療法による再狭窄の防止
    篠原 正和, KAWASHIMA, Seinosuke, 高谷 具史, YAMASHITA,Tomoya, INOUE,Nobutaka, HIRATA, Kenichi, YOKOYAMA, Mitsuhiro
    第35回日本動脈硬化学会, Sep. 2003, Japanese, 日本動脈硬化学会, 京都, Domestic conference
    Poster presentation

  • 経口BH4投与はアポEノックアウトマウスの動脈硬化形成を抑制する
    YAMASHITA,Tomoya, KAWASHIMA, Seinosuke, 尾崎 正憲, 篠原 正和, INOUE,Nobutaka, HIRATA, Kenichi, 安井 裕之, 櫻井 弘, 政田 正弘, YOKOYAMA, Mitsuhiro
    第3回日本NO学会, May 2003, Japanese, 日本NO学会, 東京, Domestic conference
    Oral presentation

■ Affiliated Academic Society
  • American Heart Association

  • JAPAN ATHEROSCLEROSIS SOCIETY

  • 日本循環器学会

  • 日本内科学会

■ Research Themes
  • Genome and single cell transcirptome analyses of atherosclerotic lesions for clarifying the pathophysiology of diseases and developing novel therapies.
    山下 智也, 江本 拓央
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2024 - 31 Mar. 2027

  • Development of novel immune therapy against abdominal aortic aneurysm.
    江本 拓央, 井上 大志, 山中 勝弘, 岡田 健次, 山下 智也
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2024 - 31 Mar. 2027

  • 虚血性心疾患法医剖検例におけるシングルセルRNAシークエンス解析
    近藤 武史, 江本 拓央, 山下 智也
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 01 Apr. 2023 - 31 Mar. 2026
    虚血性心疾患剖検例の収集を行い、死後経過時間の浅い実際の法医剖検例において、RNA が十分な品質かどうかの検討を進めた。一方、共同研究である大動脈解離手術例におけるシングルセルRNA解析については、論文投稿・改訂中である。慢性肺動脈血栓塞栓症のシングルセルRNA解析も共同研究として現在進行中である。

  • Clarifying the mechanisms of atherosclerotic cardiovascular diseases via genome and single cell integrated omics analyses.
    平田 健一, 井上 大志, 大竹 寛雅, 山中 勝弘, 江本 拓央, 岡田 健次, 山下 智也
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2023 - 31 Mar. 2026
    本研究の目的は、動脈硬化性疾患(冠動脈疾患CAD、大動脈瘤AA、大動脈弁狭窄症AS)のシングルセルアトラスの作成と全ゲノム解析を行い、トランスオミックス統合解析を行うことで、それぞれの疾患の相違点を炙り出し、疾患のリスク層別化を行い、発症メカニズムを解明することである。本研究では、これら3疾患について、1)病変部のシングルセル+核RNAシークエンス(scRNAseq+snRNAseq)からシングルセルアトラスを作成、各々の疾患特異的マクロファージの同定を行うと同時に、2)T細胞レパトア解析から各々の疾患において、特徴的な抗原が存在するのかを明らかにする。さらには、3)Genotyping of Transcriptomes (GoT)による シングルセルレベルで骨髄のクローン性造血の関与を調べる解析と4)全ゲノム解析による遺伝素因とトランスクリプトームの関連を解析する、expression quantitative locus (eQTL)解析を行う。3)と4)の実施にて、ゲノム・トランスクリプトーム統合解析が達成できる。すでに、3疾患の少数サンプルでのシングルセルトランスクリプトーム解析は終了し、シングルセルアトラスの概要は見えてきている。CADでT細胞受容体レパトア解析が終了し論文報告を行った。AAでは、結果を受けマウスでの実験も同時実施しており、マクロファージやB細胞での疾患特異的な特徴のデータを得ている。ASでのクローン性造血(CH)の原因となる体細胞遺伝子変異の解析数を増加させており、少数患者でのGoT解析を進めている。まずは3)GoTの統合解析手法の確立を目指す。全ゲノム解析は実施できておらず、4)eQTLの実施までには、さらに時間が必要と考えられる。

  • ヒト大動脈解離におけるシングルセルRNAシークエンスによる成因解析
    岡田 健次, 井上 大志, 山中 勝弘, 江本 拓央, 山下 智也
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, Apr. 2022 - Mar. 2025

  • 大動脈解離の発生と進展に好中球が与える影響の検討
    井上 大志, 山中 勝弘, 江本 拓央, 岡田 健次, 山下 智也
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, Apr. 2022 - Mar. 2025

  • Research on regulating gut bacteria to have the same effect on brown adipose tissue as exercise
    Hirata Ken-ichi
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kobe University, 30 Jun. 2022 - 31 Mar. 2024
    The purpose of this study is to search for gut bacteria with the same effect as exercise and to verify the possibility of treating obesity. In order to identify gut bacteria that increase with "exercise", obese model mice were subjected to treadmill exercise, but those exercise did not affect obesity, and it was not possible to identify the exercise-mimicking bacteria. Oral administration of Bacteroides species to fat diet loading obese model mice suppressed obesity, improved branched-chain amino acid metabolism in brown fat cells, and demonstrated the possibility of reproducing thermogenesis that occurs with exercise. By investigating the relationship between thinness/obesity and gut microbiota in humans, we found some novel evidence of gut flora type in association with thin elder person.

  • Gerontological investigation of microbiome: a longitudinal estimation study
    佐治 直樹, 山下 智也, 道川 誠, 都築 毅, 室谷 健太
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), National Center for Geriatrics and Gerontology, Apr. 2020 - Mar. 2023
    近年、腸内細菌と認知症との関連が注目されている。「腸内細菌」と「認知症」という一見接点のなさそうな組み合わせでありながら、インパクトのある関係から、世界中で研究が展開されている。これまでは見えなかった「新しい臓器」としての腸内細菌の解明が病気の予防につながり、国民の健康生活に貢献しうるため、腸内細菌についての研究を私達も進めている。 もの忘れ外来の患者さんを対象に腸内細菌についての臨床研究を実施してきた結果、①認知症と腸内細菌叢(エンテロタイプ)に有意な関連があった(Saji N, et al. Sci Rep. 2019.)。②軽度認知障害群と認知機能健常群との比較でもエンテロタイプは異なっており、認知症になる前から腸内細菌叢に変化が生じていた(Saji N, et al. Sci Rep. 2019.)。③加齢や動脈硬化を伴う生活習慣病の併存によってもエンテロタイプの割合に違いがあった(Saji N, et al. Hypertens Res. 2019.)。機序は未解明であったため、腸内細菌の代謝産物も解析した結果、④認知症群で、アンモニアなどの有機酸は増加し乳酸値は減少していた(Saji N, et al. Sci Rep. 2020.)。さらに、⑤腸内細菌は大脳白質病変(脳MRIの異常所見)とも独立して関連しており、腸内細菌と脳・認知機能に関する深い関係が判明した(Saji N, et al. J Stroke Cerebrovasc Dis. 2021.)。 現在は、腸内細菌、細菌代謝産物、認知機能、の関連を包括的に評価し、腸内細菌と認知症について関わるメカニズム解明を目標にしている。また、口腔内細菌(歯周病)と認知機能との関連についても、歯科のグループと連携して研究を展開している。

  • Development of new therapies using outer membrane vesicles derived from gut microbiota
    Yamashita Tomoya
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kobe University, Jul. 2020 - Mar. 2022
    The purpose of this study is to elucidate the biological effects of outer membrane vesicles (OMVs) derived from gut microbiota and to verify their potential application to therapy. OMVs are spherical vesicles secreted by bacteria with a lipid bilayer structure of the diameter from 20 to 250 nm, and contain various bacterial cell components including lipopolysaccharide (LPS), proteins and nucleic acids of each bacterium. We succeeded in isolating OMVs produced from cultured gut microbiota. LPS is contained in OMVs, and the pro-inflammatory activities were the same as LPS activity of each bacterium. It was confirmed that specific OMVs were produced from each bacterium. We investigated the transfer of OMVs from the intestinal tract to the blood, but we concluded that the possibility of transfer was low. Taken these, we could clarify the pathophysiological role of OMVs in vivo.

  • 循環器疾患における腸内細菌叢の役割の解明と新規治療標的の探索
    山下 智也
    学術研究助成基金助成金, 基盤研究(B), Apr. 2019 - Mar. 2022, Principal investigator
    Competitive research funding

  • Unraveling the anti-inflammatory mechanisms of human 2 Bacteroides species and their application for treating chronic inflammatory diseases.
    YAMASHITA TOMOYA
    AMED, PRIME, Oct. 2018 - Mar. 2022, Principal investigator
    Competitive research funding

  • Hirata Ken-ichi
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, Apr. 2017 - Mar. 2020
    We investigated the gut microbiota of coronary artery disease (CAD) patients and found that specific bacteria, Bacteroides vulgatus and dorei (2 species), were decreased in CAD patients. Oral administration of the cultured lived Bacteroides 2 species (5.0×109 cfu x5/week) to apolipoprotein E-deficient mice for 10 weeks significantly inhibited atherosclerotic lesion formation by reducing inflammatory responses, including plasma cytokine and lipopolysaccharide (LPS) levels. Taken these, we hypothesized that these bacteria could inhibit atherosclerosis in human and we would like to develop gut bacterial drugs using these Bacteroides 2 species.
    Competitive research funding

  • 山下 智也
    学術研究助成基金助成金/基盤研究(C), Apr. 2016 - Mar. 2019, Principal investigator
    Competitive research funding

  • 山下 智也
    科学研究費補助金/基盤研究(C), Apr. 2012 - Mar. 2015, Principal investigator
    Competitive research funding

  • SHITE Junya, YAMASHITA Tomoya
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 2009 - 2011
    We investigated the diagnostic and therapeutic methods for atherosclerotic plaque rapture in clinics. We had already reported the observational research results ; coronary arterial lesions and thrombus following sirolimus-eluting stent implantation assessed by optical coherence tomography, Effect of some drugs on the stability of coronary atherosclerotic plaques. Moreover, we developed some of the new anti-inflammatory therapies against atherosclerosis in basic experiments using mouse. We united the clinical and basical research results and discovered the drug's beneficial mechanism that the drug regressed atherosclerotic lesions or stabilized the lesions in clinical research. We could not discover the new marker for predicting the atherosclerotic plaque rapture, so far.
    Competitive research funding

  • YAMASHITA Tomoya
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 2007 - 2008, Principal investigator
    放射光を利用して、循環器疾患の診断に使用できる方法の開発を目指して研究を進めた。動脈硬化不安定粥腫の診断を目標に、位相差X線CTを共同で開発し、動物での撮影に成功し、動脈硬化の質的診断にまで到達した。また、X線回折法にての心筋症の新規診断方法を確率するための動物実験とヒトサンプルでの研究を進めた。
    Competitive research funding

■ Industrial Property Rights
  • リポ多糖制御性腸内細菌及びその用途
    山下 智也
    特願2018-022578, 09 Feb. 2018
    Patent right

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