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山下 智也大学院科学技術イノベーション研究科 科学技術イノベーション専攻教授
研究活動情報
■ 受賞- 2016年07月 日本動脈硬化学会, 五島雄一郎賞, 動脈硬化の原因としての腸管免疫と腸内細菌日本国国内学会・会議・シンポジウム等の賞
- 2011年04月 American Heart Association, 2011 Daniel Steinberg New Investigator Award in Atherosclerosis/Lipoproteins
- Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2+ macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.Springer Science and Business Media LLC, 2025年05月, Nature immunology, 26(5) (5), 706 - 721, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Both underweight and overweight are recognized as important factors influencing outcomes in patients undergoing cardiovascular surgery. This study investigated the effects of body mass index (BMI) on hospital-associated disability (HAD) and hospitalization costs in patients undergoing elective cardiovascular surgery (coronary artery bypass grafting, valve surgery, aortic surgery) by analyzing data from the Japanese Registry of All Cardiac and Vascular Diseases - Diagnosis Procedure Combination (JROAD-DPC) database. METHODS AND RESULTS: All patients in the JROAD-DPC database were categorized into 5 groups according to the World Health Organization BMI criteria for Asians. HAD was defined as a decrease of ≥5 points in the Barthel Index from admission to discharge. The primary outcome was the prevalence of HAD, and the secondary outcome was hospitalization costs. Among the 228,891 patients included in the study, the median BMI was 23.2 kg/m2. The prevalence of HAD was 8.7%, with a U-shaped relationship between BMI and HAD, indicating that both extremely low and high BMIs were associated with a higher incidence of HAD. Hospitalization costs also showed a U-shape relationship with BMI, with higher costs for patients with HAD. CONCLUSIONS: Low BMI in any age group was associated with HAD, and older people with a BMI considered too high also had HAD. BMI could be an important risk stratification tool for functional outcomes and economic burden in patients undergoing elective cardiovascular surgery.2025年03月, Circulation journal : official journal of the Japanese Circulation Society, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Body mass index (BMI) is associated with the sites of intracerebral hemorrhage (ICH), which affect functional decline. However, the optimal BMI range for minimizing functional decline remains unclear. This study aimed to clarify the relationship between BMI and ICH-related functional decline. METHODS: ICH survivors 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 categorized according to the World Health Organization Asia-Pacific classification. The primary outcome was ICH-related functional decline, defined as an increase in the modified Rankin Scale (mRS) score at discharge compared to pre-stroke. RESULTS: This study included 155,211 patients with ICH, with a mean BMI of 22.3 kg/m2. Among these patients, 74.1% experienced ICH-related functional decline. The overweight group (23.0 < BMI ≤ 25.0 kg/m2) exhibited the lowest rate of functional decline (Odds ratio: 0.90, 95% CI: 0.85-0.94). The relationship between BMI and ICH-related functional decline followed a U-shaped curve, indicating that a BMI range of 22.2-30.4 kg/m2 was associated with reduced odds of functional decline. CONCLUSION: In patients with ICH, both extremely low and high BMIs were associated with a higher likelihood of functional decline post-ICH onset. Maintaining a BMI within the range of 22.2-30.4 kg/m2 may be beneficial for reducing the risk of functional decline.2025年03月, Neurological research, 1 - 10, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S. salivarius may prevent host obesity caused by excess sucrose intake via the exopolysaccharide (EPS) -short-chain fatty acid (SCFA) -carbohydrate metabolic axis in male mice. Healthy human donor-derived S. salivarius produced high EPS levels from sucrose but not from other sugars. S. salivarius abundance was significantly decreased in human donors with obesity compared with that in healthy donors, and the EPS-SCFA bacterial carbohydrate metabolic process was attenuated. Our findings reveal an important mechanism by which host-commensal interactions in glycometabolism affect energy regulation, suggesting an approach for preventing lifestyle-related diseases via prebiotics and probiotics by targeting bacteria and EPS metabolites.2025年01月, Nature communications, 16(1) (1), 1145 - 1145, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Objectives: The pathophysiological mechanism of abdominal aortic aneurysm (AAA) remains unclear. We previously reported that Bifidobacterium adolescentis levels were reduced in the feces of patients with AAA by 16S ribosomal ribonucleic acid (RNA) gene sequencing. In this study, we increased the number of cases and conducted metagenomic analyses to examine bacterial genes associated with the pathophysiology of AAA. Methods: For gut microbiota data, feces from 55 patients with AAA and 52 patients with no history of AAA, lower extremity artery disease, or coronary artery disease (control group) were collected. Metagenomic analysis was performed by collecting raw stool samples from patients. For intestinal microbiota analysis, metagenomic analysis of the fecal samples was performed. Results: Oral bacteria, including Actinomyces oris (p <0.0001), Streptococcus salivarius (p <0.001), Lactobacillus salivarius (p <0.001), and Streptococcus sp. (p <0.001), were increased in the feces of patients with AAA. In addition, bacterial genes related to alpha lipoic acid (ALA) biosynthesis (M00882, M00883, and M00884, p <0.0001) were decreased in patients with AAA. Conclusions: In the feces of patients with AAA, there was an increase in oral bacteria, and the expression of bacterial genes related to ALA biosynthesis was reduced. The results suggest the possibility of developing gut microbial drug treatments for AAA.2025年, Annals of vascular diseases, 18(1) (1), 24 - 24, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2024年12月, Communications biology, 7(1) (1), 1601 - 1601, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Elsevier BV, 2024年12月, Clinical Nutrition, 45, 91 - 100, 英語[査読有り]研究論文（学術雑誌）
- 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.Informa UK Limited, 2024年10月, Topics in stroke rehabilitation, 1 - 10, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- The 88(th)Annual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8(th)to Sunday, March 10(th)in Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.JAPANESE CIRCULATION SOC, 2024年09月, CIRCULATION JOURNAL, 88(9) (9), 1502 - 1508, 英語研究論文（学術雑誌）
- 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.2024年06月, Scientific reports, 14(1) (1), 14893 - 14893, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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: UMIN000040747.2024年05月, Arteriosclerosis, thrombosis, and vascular biology, 44(5) (5), 1135 - 1143, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BMFH Press, 2024年, Bioscience of Microbiota, Food and Health, 43(1) (1), 64 - 72[査読有り]研究論文（学術雑誌）
- 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, 2023年08月, Glia[査読有り]研究論文（学術雑誌）
- Japanese Society of Internal Medicine, 2023年02月, Internal Medicine, 62(3) (3), 399 - 403[査読有り]研究論文（学術雑誌）
- 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), 2022年12月, Hypertension, 79(12) (12), 2821 - 2829[査読有り]研究論文（学術雑誌）
- 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.Springer Science and Business Media LLC, 2022年11月, Scientific Reports, 12(1) (1)[査読有り]研究論文（学術雑誌）
- Elsevier BV, 2022年11月, International Journal of Cardiology, 367, 38 - 44[査読有り]研究論文（学術雑誌）
- Elsevier BV, 2022年10月, Atherosclerosis, 358, 1 - 11[査読有り]研究論文（学術雑誌）
- 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.2022年07月, Heliyon, 8(7) (7), e09981, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2022年05月, Circulation, 145(18) (18), 1434 - 1436, 英語, 国際誌[査読有り]
- Anticancer Research USA Inc., 2022年03月, Anticancer Research, 42(3) (3), 1589 - 1598[査読有り]研究論文（学術雑誌）
- 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年, Journal of Alzheimer's disease : JAD, 86(4) (4), 1947 - 1957, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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年, Bioscience of microbiota, food and health, 41(2) (2), 45 - 53, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2021年11月, iScience, 24(11) (11), 103342 - 103342, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2021年09月, International journal of cardiology, 338, 138 - 142, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2021年08月, Heart and vessels, 36(8) (8), 1234 - 1245, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2021年07月, Circulation reports, 3(7) (7), 375 - 380, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2021年04月, Toxins, 13(5) (5), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2021年04月, Journal of atherosclerosis and thrombosis, 28(4) (4), 314 - 316, 英語, 国内誌研究論文（学術雑誌）
- 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.2021年04月, Journal of cardiovascular electrophysiology, 32(4) (4), 1035 - 1043, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2021年, Frontiers in cardiovascular medicine, 8, 789325 - 789325, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2021年01月, Heart and vessels, 36(1) (1), 105 - 114, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2021年01月, Journal of diabetes investigation, 12(1) (1), 123 - 129, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2020年12月, Heart and vessels, 35(12) (12), 1717 - 1726, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2020年09月, Annals of translational medicine, 8(17) (17), 1059 - 1059, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.Springer Science and Business Media LLC, 2020年08月, Scientific reports, 10(1) (1), 13009 - 13009, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2019年10月, Journal of cardiology, 74(4) (4), 360 - 365, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2019年08月, Journal of atherosclerosis and thrombosis, 26(8) (8), 705 - 719, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2019年05月, Scientific reports, 9(1) (1), 8065 - 8065, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2018年12月, Circulation journal : official journal of the Japanese Circulation Society, 83(1) (1), 182 - 192, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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: UMIN000015703.2018年11月, Circulation, 138(22) (22), 2486 - 2498, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2018年06月, Data in brief, 18, 172 - 175, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2018年02月, Atherosclerosis, 269, 245 - 251, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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年, Internal Medicine, 57(8) (8), 1111 - 1114, 英語[査読有り]研究論文（学術雑誌）
- 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.2017年08月, Journal of the American Heart Association, 6(9) (9), e007024, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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, 2017年08月, CARDIOVASCULAR DIABETOLOGY, 16(1) (1), 96, 英語[査読有り]研究論文（学術雑誌）
- 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.2017年06月, Heart and vessels, 32(6) (6), 768 - 776, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2017年03月, Journal of cardiology cases, 15(3) (3), 100 - 103, 英語, 国内誌
. [査読有り] - 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, 2017年03月, JOURNAL OF LIPID RESEARCH, 58(3) (3), 519 - 528, 英語[査読有り]研究論文（学術雑誌）
- 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, 2017年01月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 37(1) (1), 66 - +, 英語[査読有り]研究論文（学術雑誌）
- 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, 2017年01月, EUROPACE, 19(1) (1), 40 - 47, 英語[査読有り]研究論文（学術雑誌）
- 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.SPRINGER, 2017年01月, HEART AND VESSELS, 32(1) (1), 39 - 46, 英語[査読有り]研究論文（学術雑誌）
- 2016年10月, Europace, 19(19) (19), 40 - 47, 英語Monocyte-to-HDL-cholesterol ratio and left atrial remodelling in atrial fibrillation: author's reply[査読有り]研究論文（学術雑誌）
- 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, 2016年06月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 36(6) (6), 1141 - U224, 英語[査読有り]研究論文（学術雑誌）
- 一般社団法人 日本内科学会, 2016年, 日本内科学会雑誌, 105(9) (9), 1706 - 1711, 日本語
- 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.JAPAN ATHEROSCLEROSIS SOC, 2016年, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 23(8) (8), 908 - +, 英語[査読有り]研究論文（学術雑誌）
- Japanese Journal of Clinical Chemistry, 2015年10月, Japanese Journal of Clinical Chemistry, 44(4) (4), 282 - 289, 日本語Gut microbiota and cardiovascular disease研究論文（学術雑誌）
- 2015年10月, 薬理と治療, 43(10号) (10号), 1409 - 1416, 日本語アンジオテンシン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[査読有り]研究論文（その他学術会議資料等）
- 2015年06月, Bone Marrow Transplantation, 50(6) (6), 870 - 872, 英語[査読有り]研究論文（学術雑誌）
- 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, 2015年04月, HYPERTENSION, 65(4) (4), 889 - +, 英語[査読有り]研究論文（学術雑誌）
- Investigation of the differential effects of n-3 polyunsaturated fatty acids, EPA and DHA, on angiotensin II-induced aortic aneurysm formation in miceBackground 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年, Japanese Pharmacology and Therapeutics, 43(10) (10), 1409 - 1416, 日本語研究論文（学術雑誌）
- 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, 2014年12月, CIRCULATION JOURNAL, 78(12) (12), 2935 - 2941, 英語[査読有り]研究論文（学術雑誌）
- 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, 2014年11月, CLINICAL ANATOMY, 27(8) (8), 1200 - 1211, 英語[査読有り]研究論文（学術雑誌）
- [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]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.2014年06月, Rinsho Ketsueki, 55(6) (6), 697 - 702, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 2014年06月, 臨床血液, 55(6号) (6号), 697 - 702, 日本語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[査読有り]研究論文（学術雑誌）
- 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, 2014年04月, CARDIOVASCULAR RESEARCH, 102(1) (1), 107 - 117, 英語[査読有り]研究論文（学術雑誌）
- 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, 2014年04月, JOURNAL OF VASCULAR SURGERY, 59(4) (4), 1098 - 1108, 英語[査読有り]研究論文（学術雑誌）
- 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, 2014年04月, JOURNAL OF THE AMERICAN HEART ASSOCIATION, 3(2) (2), e000719, 英語[査読有り]研究論文（学術雑誌）
- 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年, INTERNAL MEDICINE, 52(1) (1), 71 - 74, 英語[査読有り]研究論文（学術雑誌）
- 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, 2012年09月, PLOS ONE, 7(9) (9), e45361, 英語[査読有り]研究論文（学術雑誌）
- 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.SPRINGER, 2012年06月, INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, 28(5) (5), 1181 - 1191, 英語[査読有り]研究論文（学術雑誌）
- Expression of Endothelial Lipase Correlates with the Size of Neointima in a Murine Model of Vascular RemodelingAim: 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年, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(12) (12), 1110 - 1127, 英語[査読有り]研究論文（学術雑誌）
- 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.)LIPPINCOTT WILLIAMS & WILKINS, 2011年09月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 31(9) (9), 1963 - U124, 英語[査読有り]研究論文（学術雑誌）
- 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, 2011年08月, AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 205(2) (2), 英語[査読有り]研究論文（学術雑誌）
- 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.)LIPPINCOTT WILLIAMS & WILKINS, 2010年12月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 30(12) (12), 2495 - U305, 英語[査読有り]研究論文（学術雑誌）
- 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, 2009年11月, CIRCULATION, 120(20) (20), 1996 - U43, 英語研究論文（学術雑誌）
- Plasma Tetrahydrobiopterin/Dihydrobiopterin Ratio - A Possible Marker of Endothelial DysfunctionBackground: 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, 2009年05月, CIRCULATION JOURNAL, 73(5) (5), 955 - 962, 英語[査読有り]研究論文（学術雑誌）
- 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 synthaseBackground 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, 2008年09月, CIRCULATION JOURNAL, 72(9) (9), 1512 - 1519, 英語[査読有り]研究論文（学術雑誌）
- 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, 2008年06月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 28(6) (6), 1068 - 1076, 英語[査読有り]研究論文（学術雑誌）
- 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, 2008年02月, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 294(2) (2), H1094 - H1100, 英語[査読有り]研究論文（学術雑誌）
- 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, 2007年11月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 27(11) (11), 2384 - 2391, 英語[査読有り]研究論文（学術雑誌）
- 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, 2007年09月, AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 293(3) (3), C865 - C873, 英語[査読有り]研究論文（学術雑誌）
- 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, 2007年08月, CIRCULATION, 116(9) (9), 1041 - 1051, 英語[査読有り]研究論文（学術雑誌）
- 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, 2007年07月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 27(7) (7), 1632 - 1637, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年09月, RESPIROLOGY, 11(5) (5), 546 - 556, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年09月, CIRCULATION RESEARCH, 99(7) (7), E51 - E64, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年07月, INTERNATIONAL IMMUNOPHARMACOLOGY, 6(7) (7), 1040 - 1052, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年06月, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 290(6) (6), L1078 - L1086, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年06月, ATHEROSCLEROSIS, 186(2) (2), 402 - 410, 英語[査読有り]研究論文（学術雑誌）
- 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, 2006年03月, BIOPHYSICAL JOURNAL, 90(5) (5), 1723 - 1728, 英語[査読有り]研究論文（学術雑誌）
- 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, 2005年11月, CARDIOVASCULAR RESEARCH, 68(2) (2), 249 - 258, 英語研究論文（学術雑誌）
- 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, 2004年10月, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(43) (43), 45085 - 45092, 英語[査読有り]研究論文（学術雑誌）
- 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, 2004年01月, ATHEROSCLEROSIS, 172(1) (1), 21 - 29, 英語[査読有り]研究論文（学術雑誌）
- 2003年09月, 日本動脈硬化学会総会プログラム・抄録集, pp. 211-211, 日本語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研究論文（国際会議プロシーディングス）
- 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, 2003年01月, STROKE, 34(1) (1), 157 - 163, 英語[査読有り]研究論文（学術雑誌）
- A 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor reduces hypertensive nephrosclerosis in stroke-prone spontaneously hypertensive ratsBackground 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, 2002年12月, JOURNAL OF HYPERTENSION, 20(12) (12), 2465 - 2473, 英語[査読有り]研究論文（学術雑誌）
- 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, 2002年12月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(12) (12), 2049 - 2053, 英語[査読有り]研究論文（学術雑誌）
- In vivo angiographic detection of vascular lesions in apolipoprotein E-knockout mice using a synchrotron radiation microangiography systemGenetically 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, 2002年11月, CIRCULATION JOURNAL, 66(11) (11), 1057 - 1059, 英語[査読有り]研究論文（学術雑誌）
- Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusionEndogenous 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, 2002年09月, CIRCULATION JOURNAL, 66(9) (9), 851 - 856, 英語[査読有り]研究論文（学術雑誌）
- 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, 2002年06月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(6) (6), 969 - 974, 英語[査読有り]研究論文（学術雑誌）
- Overexpression of endothelial nitric oxide synthase in endothelial cells is protective against ischemia-reperfusion injury in mouse skeletal muscleMicrovascular 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, 2002年04月, AMERICAN JOURNAL OF PATHOLOGY, 160(4) (4), 1335 - 1344, 英語[査読有り]研究論文（学術雑誌）
- 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年, Journal of Clinical Investigation, 110(3) (3), 331 - 340, 英語研究論文（学術雑誌）
- 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, 2002年01月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22(1) (1), 115 - 120, 英語[査読有り]研究論文（学術雑誌）
- 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, 2001年10月, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 5(5) (5), 494 - 503, 英語[査読有り]研究論文（学術雑誌）
- A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide productionObjective 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, 2001年03月, JOURNAL OF HYPERTENSION, 19(3) (3), 451 - 458, 英語[査読有り]研究論文（学術雑誌）
- Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endotheliumWe 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, 2001年02月, HYPERTENSION, 37(2) (2), 322 - 327, 英語[査読有り]研究論文（学術雑誌）
- Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodelingNO 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, 2001年02月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 21(2) (2), 201 - 207, 英語[査読有り]研究論文（学術雑誌）
- Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbitsStudies 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, 2001年01月, ATHEROSCLEROSIS, 154(1) (1), 87 - 96, 英語[査読有り]研究論文（学術雑誌）
- Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthaseNO, 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, 2000年07月, HYPERTENSION, 36(1) (1), 97 - 102, 英語[査読有り]研究論文（学術雑誌）
- 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, 2000年06月, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 32(6) (6), 947 - 960, 英語[査読有り]研究論文（学術雑誌）
- 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, 2000年04月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 20(4) (4), 1006 - 1012, 英語[査読有り]研究論文（学術雑誌）
- Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthaseBackground-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, 2000年02月, CIRCULATION, 101(8) (8), 931 - 937, 英語[査読有り]研究論文（学術雑誌）
- 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, 1998年12月, Journal of Clinical Investigation, 102(12) (12), 2061 - 2071, 英語[査読有り]研究論文（学術雑誌）
- ＜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), 2024年11月, 医学のあゆみ, 291(5) (5), 388 - 394, 日本語
- 【慢性炎症と心血管疾患】腸内細菌と心血管疾患臨床・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, 2024年11月, 別冊Bio Clinica: 慢性炎症と疾患, 13(2) (2), 54 - 59, 日本語
- (株)メディカ出版, 2024年10月, Nutrition Care, 17(10) (10), 952 - 957, 日本語
- (一社)日本内科学会, 2024年09月, 日本内科学会雑誌, 113(9) (9), 1525 - 1532, 日本語腸内細菌と心血管疾患
- (一社)日本内科学会, 2024年02月, 日本内科学会雑誌, 113(臨増) (臨増), 82 - 85, 日本語腸内細菌と心血管疾患
- (公財)ヤクルト・バイオサイエンス研究財団, 2023年09月, 腸内フローラシンポジウム, 30, 47 - 56, 日本語腸内細菌と循環器疾患
- (一社)日本臨床化学会, 2023年07月, 臨床化学, 52(3) (3), 170 - 178, 日本語
- (一社)日本腎臓学会, 2023年03月, 日本腎臓学会誌, 65(2) (2), 87 - 94, 日本語【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
- 2023年, 心臓, 55(4) (4)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
- (公財)日本心臓財団, 2022年02月, 心臓, 54(2) (2), 279 - 288, 日本語
- 2022年, 日本臨床生理学会雑誌, 52(3) (3)循環器疾患と腸内細菌
- 2022年, 臨床検査, 66(11) (11)マイクロバイオーム Microbiomeと心血管系疾患
- 2022年, 循環器専門医, 31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
- 2022年, 循環器専門医, 31基礎科学の進歩 腸内細菌と循環器疾患
- 2022年, 循環器内科, 92(5) (5)大動脈疾患,末梢動脈疾患の最新トピックス 大動脈瘤の進展における腸内細菌の役割
- 2022年, 医学のあゆみ, 283(14) (14)慢性炎症・多臓器関連・メカニカルストレスから捉える循環器疾患 腸内細菌は循環器疾患の原因か
- 2022年, ICUとCCU, 46(12) (12)循環器集中治療フラグ(伏線を探る)腸内細菌叢と心血管疾患
- (一社)日本内科学会, 2021年09月, 日本内科学会雑誌, 110(9) (9), 1848 - 1854, 日本語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
- 【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, 2021年09月, カレントテラピー, 39(9) (9), 844 - 846, 日本語
- ＜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, 2021年06月, Heart View, 25(6) (6), 520 - 525, 日本語
- (一社)日本内科学会, 2021年02月, 日本内科学会雑誌, 110(Suppl.) (Suppl.), 93 - 94, 日本語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
- シスメックス(株)学術本部, 2021年, シスメックス学術セミナー, 43回, 55 - 65, 日本語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
- シスメックス(株)学術本部, 2021年, Sysmex Journal Web, 22(1) (1), 8 - 9, 日本語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
- (株)医学書院, 2021年01月, Medicina, 58(1) (1), 64 - 68, 日本語
- (公社)日本医師会, 2020年12月, 日本医師会雑誌, 149(9) (9), 1583 - 1587, 日本語【腸内細菌と疾患】腸内細菌と循環器疾患
- (株)メディカルレビュー社, 2020年12月, Pharma Medica, 38(12) (12), 57 - 60, 日本語
- ＜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, 2020年09月, 内科, 126(3) (3), 434 - 437, 日本語
- (一社)日本循環器学会, 2020年07月, 日本循環器学会学術集会抄録集, 84回, シンポジウム19 - 4, 英語心不全と栄養(Gut Microbiota and Their Related Metabolites in Heart Failure as Novel Therapeutic Targets)
- (有)科学評論社, 2020年06月, 循環器内科, 87(6) (6), 734 - 740, 日本語
- (一社)日本糖尿病学会, 2020年06月, 糖尿病, 63(6) (6), 382 - 385, 日本語
- (有)科学評論社, 2020年05月, 循環器内科, 87(5) (5), 550 - 556, 日本語
- (株)ライフ・サイエンス, 2020年03月, Progress in Medicine, 40(3) (3), 223 - 229, 日本語
- 2020年03月, PROGRESS IN MEDICINE, 40(3) (3), 31 - 37, 日本語循環器疾患と腸内細菌叢[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 日本心脈管作動物質学会, 2020年01月, 血管, 43(1) (1), 30 - 30, 日本語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
- (株)メディカ出版, 2020年01月, 糖尿病ケア, 17(1) (1), 31 - 33, 日本語記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- ＜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, 2020年01月, 循環器ジャーナル, 68(1) (1), 156 - 160, 日本語記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- ＜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, 2020年01月, 循環器ジャーナル, 68(1) (1), 161 - 164, 日本語記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (公社)日本医師会, 2019年10月, 日本医師会雑誌, 148(特別2) (特別2), S326 - S328, 日本語【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
- 循環器疾患と腸内細菌叢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。(一財)医薬品医療機器レギュラトリーサイエンス財団, 2019年09月, 医薬品医療機器レギュラトリーサイエンス, 50(9) (9), 504 - 512, 日本語[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (一社)日本心臓病学会, 2019年09月, 日本心臓病学会学術集会抄録, 67回(14号) (14号), T3 - T3, 日本語腸内細菌と循環器疾患[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (一社)日本循環器学会, 2019年08月, 循環器専門医, 28, 81 - 84, 日本語記事・総説・解説・論説等（学術雑誌）
- 2019年04月, カレントテラピー, 37(4) (4), 388 - 394, 日本語動脈硬化と腸内細菌記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2019年03月, モダンメディア, 65(3) (3), 49 - 53, 日本語腸内細菌叢 腸内細菌と動脈硬化性疾患記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2019年02月, Cardiac Practice, 29(4) (4), 29 - 32, 日本語動脈硬化性疾患と腸内細菌叢記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 【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), 2019年02月, 医学のあゆみ, 268(5) (5), 343 - 348, 日本語[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年12月, 日本臨床, 76(増刊9 心不全(上)) (増刊9 心不全(上)), 358 - 362, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (有)科学評論社, 2018年11月, 循環器内科, 84(5) (5), 584 - 590, 日本語腸管免疫・腸内細菌叢と冠動脈疾患[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (株)ライフメディコム, 2018年11月, カレントテラピー, 36(11) (11), 1116 - 1121, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年10月, The Lipid, 29(4号) (4号), 384 - 391, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年09月, 日本内科学会雑誌, 107(9号) (9号), 1906 - 1912, 日本語腸内細菌と循環器疾患[査読有り]記事・総説・解説・論説等（学術雑誌）
- 2018年09月, Circ J, 82(10) (10), 2470 - 2471, 英語Bicuspid Aortic Valve-Associated Aortic Dilatation - What Is the Mechanism of Bicuspid Aortopathy[査読有り]記事・総説・解説・論説等（学術雑誌）
- 2018年08月, 循環plus, 18(6号) (6号), 10 - 12, 日本語病態連関の新知見 腸内細菌と動脈硬化記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年08月, 循環器専門医, 27, 3 - 8, 日本語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記事・総説・解説・論説等（学術雑誌）
- 2018年07月, 循環器内科, 84(1号) (1号), 86 - 92, 日本語心房細動・心不全と腸内細菌記事・総説・解説・論説等（学術雑誌）
- 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.2018年06月29日, Diseases (Basel, Switzerland), 6(3) (3), 英語, 国際誌[査読有り]
- 2018年06月25日, 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), 日本語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
- (一社)日本動脈硬化学会, 2018年06月, 日本動脈硬化学会総会プログラム・抄録集, 50回, 262 - 262, 日本語紫外線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
- 2018年05月25日, Circulation journal : official journal of the Japanese Circulation Society, 82(6) (6), 1507 - 1509, 英語, 国内誌[査読有り]記事・総説・解説・論説等（学術雑誌）
- 2018年02月, アンチ・エイジング医学, 14(1号) (1号), 045 - 050, 日本語【腸とアンチエイジング】 動脈硬化と腸内環境[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2018年02月, 化学療法の領域, 34(3号) (3号), 433 - 440, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年01月, 医学のあゆみ, 264(1号) (1号), 88 - 93, 日本語【腸内細菌と臨床医学】 循環器疾患と腸内細菌[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27M‐pm18, 日本語紫外線照射による動脈硬化性疾患に対する抑制効果
- 2017年11月, DM Ensemble, 6(3号) (3号), 40 - 44, 日本語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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年11月, Clinical Neuroscience, 35(11号) (11号), 1312 - 1315, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 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, 2017年11月, ファルマシア, 53(11) (11), 1073 - 1076, 日本語[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年10月, Medical Technology, 45(10号) (10号), 1038 - 1042, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年10月, 日本医科大学医学会雑誌, 13(4号) (4号), 205 - 209, 日本語【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[招待有り]記事・総説・解説・論説等（学術雑誌）
- OXFORD UNIV PRESS, 2017年08月, EUROPACE, 19(8) (8), 1409 - 1410, 英語速報，短報，研究ノート等（学術雑誌）
- 2017年08月, 医療と検査機器・試薬, 40(4号) (4号), 277 - 282, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年08月, The GI Forefront, 13(1号) (1号), 29 - 32, 日本語【腸内フローラ研究の最前線】 動脈硬化と腸内フローラ[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 科学評論社, 2017年07月, 内分泌・糖尿病・代謝内科 = Endocrinology, diabetology & metabolism, 45(1) (1), 68 - 73, 日本語腸内細菌は動脈硬化モデルマウスにおいて脂質代謝と慢性炎症を制御する[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年07月, 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, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年06月, 糖尿病診療マスター, 15(6号) (6号), 504 - 509, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (株)医学出版, 2017年05月, 月刊糖尿病, 9(5) (5), 34 - 42, 日本語【腸内細菌と生活習慣病】腸内細菌と循環器疾患[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年05月, THE LUNG-perspectives, 25(2号) (2号), 184 - 188, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年04月, Diabetes Frontier, 28(2号) (2号), 158 - 162, 日本語【消化管と糖尿病】 腸内細菌と動脈硬化[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2017年03月, 動脈硬化予防, 16(1号) (1号), 90 - 93, 日本語危険因子 腸内細菌叢(腸内フローラ)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 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年, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 24(2) (2), 110 - 119, 英語[査読有り]書評論文,書評,文献紹介等
- 2016年11月, 医学のあゆみ, 259(6号) (6号), 597 - 603, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年11月, カレントテラピー, 34(11) (11), 1089 - 1094, 日本語腸内細菌と諸疾患-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記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年09月, 動脈硬化予防, 15(3号) (3号), 89 - 91, 日本語注目される用語の解説 制御性T細胞[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年09月, 日本内科学会雑誌, 105(9号) (9号), 1706 - 1711, 日本語腸内細菌と疾患 腸内細菌と循環器疾患[招待有り]記事・総説・解説・論説等（学術雑誌）
- 最新医学社, 2016年09月, 最新医学, 71(9) (9), 1795 - 1801, 日本語腸内細菌と循環器疾患 (特集 腸内細菌学の新潮流 : 基礎医学的見地から新規治療開発まで)[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年06月, 最新冠動脈疾患学(上), 74(4) (4), 211 - 2106, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 診断と治療社, 2016年02月, 診断と治療, 104(2) (2), 171 - 174, 日本語腸内細菌と動脈硬化 (特集 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)[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年, The Lipid, 27(2) (2), 159 - 164, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年01月, カレントテラピー, 34(1号) (1号), 33 - 38, 日本語【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 腸内細菌叢と肥満記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 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年, International Heart Journal, 57(6) (6), 663 - 671, 英語[査読有り]書評論文,書評,文献紹介等
- 東京医学社, 2015年12月, 成人病と生活習慣病 : 日本成人病(生活習慣病)学会準機関誌, 45(12) (12), 1523 - 1529, 日本語腸内細菌と動脈硬化 (特集 腸内細菌は病気とどう関連するか)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 医学書院, 2015年12月, 呼吸と循環, 63(12) (12), 1209 - 1215, 日本語Bedside Teaching 動脈硬化と腸内細菌記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2015年10月, Pharma Medica, 33(10号) (10号), 23 - 26, 日本語【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記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2015年10月, 血管医学, 16(3号) (3号), 237 - 242, 日本語【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記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2015年10月, 臨床化学, 44(4号) (4号), 282 - 289, 日本語【ヒトマイクロバイオーム研究UPDATE】 腸内細菌と循環器疾患記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 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, 2015年09月, CIRCULATION JOURNAL, 79(9) (9), 1882 - 1890, 英語書評論文,書評,文献紹介等
- 2015年09月, 循環器専門医, 23(2号) (2号), 189 - 195, 日本語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記事・総説・解説・論説等（学術雑誌）
- 先端医学社, 2015年09月, Thrombosis medicine, 5(3) (3), 221 - 226, 日本語一酸化窒素(NO) (特集 血管内皮細胞関連因子)[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 医学書院, 2015年09月, 呼吸と循環, 63(9) (9), 840 - 846, 日本語腸管免疫・腸内細菌の治療介入による動脈硬化性疾患予防の展望 (特集 スタチン投与後のレジデュアル・リスク)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 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), 2015年07月01日, Journal of Cardiology, 66(1) (1), 1 - 8, 英語書評論文,書評,文献紹介等
- 2015年06月, 別冊Bio Clinica: 慢性炎症と疾患, 4(2号) (2号), 50 - 55, 日本語【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記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2015年04月, 動脈硬化予防, 14(1号) (1号), 58 - 64, 日本語【動脈硬化予防の新たなバイオマーカー】 腸内細菌叢記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- ELSEVIER SCIENCE INC, 2015年03月, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 65(10) (10), A466 - A466, 英語研究発表ペーパー・要旨（国際会議）
- Regulatory T Cells and Tolerogenic Dendritic Cells as Critical Immune Modulators in AtherogenesisInnate 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年, CURRENT PHARMACEUTICAL DESIGN, 21(9) (9), 1107 - 1117, 英語書評論文,書評,文献紹介等
- 2014年12月, メディカル朝日, 43(12号) (12号), 34 - 35, 日本語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?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 科学評論社, 2014年11月, 内分泌・糖尿病・代謝内科, 39(5) (5), 415 - 421, 日本語短鎖脂肪酸と生活習慣病 (特集 糖・脂質・エネルギー代謝の司令塔としての消化管)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年10月, 医学のあゆみ, 251(1号) (1号), 100 - 106, 日本語【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記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年09月, Therapeutic Research, 35(9号) (9号), 789 - 791, 日本語腸内細菌と代謝障害 腸内細菌と動脈硬化[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年07月, 日本循環制御医学会総会プログラム・抄録集 35回, 41, 日本語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会議報告等
- エヌ・ティー・エス, 2014年07月, 遺伝 : 生物の科学, 68(4) (4), 358 - 362, 日本語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 (特集 腸の世界 : 腸内フローラ(細菌叢)と健康・疾病) -- (腸内フローラと疾病)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 科学評論社, 2014年06月, 循環器内科, 75(6) (6), 610 - 617, 日本語腸内細菌と心血管病記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年05月, 日本老年医学会雑誌, 51(Suppl.) (Suppl.), 33, 日本語腸から動脈硬化を予防する会議報告等
- 学研メディカル秀潤社 ; 1982-, 2014年04月, 細胞工学, 33(5) (5), 486 - 488, 日本語OVERVIEW (特集 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)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 日本肥満学会, 2014年04月, 肥満研究 = Journal of Japan Society for the Study of Obesity : 日本肥満学会誌, 20(1) (1), 7 - 12, 日本語腸内細菌と動脈硬化 : 腸から動脈硬化は予防できるのか? (特集 我々にとって腸内細菌とは何なのか? : "借景"からのヒント)記事・総説・解説・論説等（学術雑誌）
- 2014年04月, The Lipid, 25(2号) (2号), 122 - 128, 日本語【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細胞記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年03月, 臨床と微生物, 41(2号) (2号), 157 - 163, 日本語【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 動脈硬化記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年03月, 実験医学, 32(5号) (5号), 773 - 779, 日本語【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?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2014年, 日本循環器学会近畿地方会(Web), 118th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
- 2014年01月, 血管, 37(1号) (1号), 20, 日本語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・治療戦略会議報告等
- 腸管は栄養や水分を吸収するのが主な機能の臓器ではあるが，免疫臓器としての役割とその重要性が注目されている．最近の研究の進展によって，腸内細菌の種類と腸管免疫調節との関係，そして常在腸内細菌叢（腸内フローラ）と疾患発症との関連性が解明されつつある．特に，腸内細菌叢と肥満，そして糖尿病をはじめとする代謝性疾患の発症との関連性が報告されており，疾患の予防を目的とした治療的介入も視野に入れた研究が進められている．同様に，動脈硬化研究の領域でも，腸内細菌叢の病態への関与や，腸管免疫修飾による新規予防法の取り組みなどの報告があり，我々も腸管からの動脈硬化予防法の開発研究を進めている．本稿では腸管と動脈硬化との関連性に注目して，今まで報告された研究成果をふまえて，今後のこの研究分野の展望について考えてみたい．JAPAN BIFIDUS FOUNDATION, 2014年01月, 腸内細菌学雑誌, 28(1) (1), 1 - 5, 日本語[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2014年01月, 血管, 37(1号) (1号), 36, 日本語抗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会議報告等
- 2014年01月, 血管, 37(1号) (1号), 36, 日本語アンジオテンシンII負荷腹部大動脈瘤マウスモデルにおける制御性T細胞の役割の検討会議報告等
- LIPPINCOTT WILLIAMS & WILKINS, 2013年11月, CIRCULATION, 128(22) (22), 英語Activation of Skin Dendritic Cells Controls Atherogensis in Mice研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2013年11月, CIRCULATION, 128(22) (22), 英語A Novel Combination Therapy with Anti-CD3 Antibody and IL-2 Complexes Against Atherosclerosis Targeting Effector T Cells and Regulatory T Cells研究発表ペーパー・要旨（国際会議）
- 社団法人日本循環器学会, 2013年09月25日, 循環器専門医 : 日本循環器学会専門医誌, 21(2) (2), 291 - 296, 日本語腸管は心血管病予防の新たな治療ターゲットになる(8.心臓と他臓器のコミュニケーションを探る-臓器連関から考える新しい循環器病治療戦略,<特集>第77回日本循環器学会学術集会)記事・総説・解説・論説等（学術雑誌）
- 2013年06月, 日本臨床, 71(増刊3 脂質異常症) (増刊3 脂質異常症), 689 - 692, 日本語【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[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2013年04月, 医学のあゆみ, 245(2号) (2号), 189 - 190, 日本語循環器内科学 腸管免疫修飾による動脈硬化予防[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2013年04月, 腸内細菌学雑誌, 27(2号) (2号), 93 - 94, 日本語原因不明疾患と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[招待有り]記事・総説・解説・論説等（学術雑誌）
- 中外医学社, 2013年01月, Annual review. 糖尿病・代謝・内分泌, 2013, 211 - 216, 日本語腸内環境と動脈硬化 (内分泌) -- (臨床分野での進歩)[査読有り][招待有り]記事・総説・解説・論説等（学術雑誌）
- LIPPINCOTT WILLIAMS & WILKINS, 2012年11月, CIRCULATION, 126(21) (21), 英語Activation of Regulatory T Cells by Ultraviolet Irradiation Controls Atherogenesis in Mice研究発表ペーパー・要旨（国際会議）
- 2012年07月, 日本動脈硬化学会総会プログラム・抄録集, (44回) (44回), 166, 日本語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会議報告等
- Regulatory T Cells in AtherogenesisAtherosclerosis 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年, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(6) (6), 503 - 515, 英語[査読有り]書評論文,書評,文献紹介等
- Dendritic Cells in Atherogenesis: Possible Novel Targets for Prevention of AtherosclerosisAtherosclerosis 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年, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 19(11) (11), 953 - 961, 英語[査読有り]書評論文,書評,文献紹介等
- 2011年, 日本循環器学会近畿地方会(Web), 112th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
- 日本臨床社, 2011年01月, 日本臨床, 69(1) (1), 168 - 172, 日本語抗動脈硬化免疫療法 (特集 炎症と動脈硬化--基礎・臨床研究の最新動向)
- LIPPINCOTT WILLIAMS & WILKINS, 2009年11月, CIRCULATION, 120(18) (18), S1067 - S1068, 英語Oral Administration of an Active Form Vitamin D-3 Decreases Atherosclerosis in Mice via Modulating Immune Cell Phenotypes and Functions研究発表ペーパー・要旨（国際会議）
- 先端医学社, 2009年01月, Vascular medicine, 5(1) (1), 66 - 70, 日本語知っておきたい血管医学用語(27)Dendritic cell(樹状細胞)
- KARGER, 2009年, JOURNAL OF VASCULAR RESEARCH, 46, 158 - 158, 英語PLASMA TETRAHYDROBIOPTERIN DIHYDROBIOPTERIN RATIO: A POSSIBLE MARKER OF ENDOTHELIAL DYSFUNCTION研究発表ペーパー・要旨（国際会議）
- 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, 2007年12月, NUTRITION REVIEWS, 65(12) (12), S182 - S187, 英語[査読有り]記事・総説・解説・論説等（学術雑誌）
- LIPPINCOTT WILLIAMS & WILKINS, 2007年10月, CIRCULATION, 116(16) (16), 146 - 146, 英語Oral Anti-CD3 antibody treatment induces CD4+LAP+ regulatory T cells and ameliorates the development of atherosclerosis in mice研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2007年10月, CIRCULATION, 116(16) (16), 769 - 769, 英語Atherosclerotic plaque imaging using phase-contrast X-ray computed tomography[査読有り]研究発表ペーパー・要旨（国際会議）
- 2007年07月, 綜合臨床, 56巻, 7, pp. 2298-2302, 日本語【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記事・総説・解説・論説等（学術雑誌）
- 2007年06月, 日本医師会雑誌, 136巻, , pp. 104-106, 日本語【メタボリックシンドロームup to date】 基礎 血管内皮記事・総説・解説・論説等（学術雑誌）
- 社団法人日本循環器学会, 2007年03月01日, Circulation journal : official journal of the Japanese Circulation Society, 71, 13 - 13, 英語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)
- 2007年03月, Heart View, 11巻, 3号, pp. 306-310, 日本語【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記事・総説・解説・論説等（学術雑誌）
- 2007年01月, Annual Review循環器, 2007巻, pp. 115-120, 日本語診断と治療 最近の進歩 虚血性心疾患 EPAの効果記事・総説・解説・論説等（学術雑誌）
- LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, CIRCULATION, 114(18) (18), 152 - 152, 英語Augmentation of vascular remodeling due to uncoupled eNOS in diabetes研究発表ペーパー・要旨（国際会議）
- CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2005年12月, JOURNAL OF CARDIAC FAILURE, 11(9) (9), S292 - S292, 英語An X-ray diffraction study on mouse cardiac cross-bridge function in vivo: Effects of adrenergic beta-stimulation研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2005年10月, CIRCULATION, 112(17) (17), U225 - U225, 英語Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2005年10月, CIRCULATION, 112(17) (17), U325 - U325, 英語An x-ray diffraction study on mouse cardiac cross-bridge function in vivo: Effects of adrenergic beta-stimulation研究発表ペーパー・要旨（国際会議）
- ELSEVIER IRELAND LTD, 2005年04月, ATHEROSCLEROSIS SUPPLEMENTS, 6(1) (1), 45 - 45, 英語Telmisartan reduces atherosclerotic lesion formation by decreasing superoxide generation in apolipoprotein E-deficient mice研究発表ペーパー・要旨（国際会議）
- ELSEVIER SCIENCE INC, 2005年02月, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 45(3) (3), 257A - 257A, 英語In vivo evaluation of X-ray diffraction from the left ventricular wall of mouse hearts研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2004年10月, CIRCULATION, 110(17) (17), 179 - 179, 英語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研究発表ペーパー・要旨（国際会議）
- ACADEMIC PRESS INC ELSEVIER SCIENCE, 2004年08月, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 11(1) (1), 63 - 64, 英語Overexpression of endothelial nitric oxide synthase deteriorates vascular remodeling in apoE-deficient mice研究発表ペーパー・要旨（国際会議）
- ACADEMIC PRESS INC ELSEVIER SCIENCE, 2004年08月, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 11(1) (1), 64 - 64, 英語GTPCH I overexpression decreases atherosclerotic lesion formation in apolipoprotein E-deficient/eNOS transgenic mice研究発表ペーパー・要旨（国際会議）
- 2004年05月, 実験医学, 22巻, 8号, pp. 1215-1220, 日本語【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記事・総説・解説・論説等（学術雑誌）
- 2004年02月, 血管医学, 5巻, 1号, pp. 11-16, 日本語【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記事・総説・解説・論説等（学術雑誌）
- 社団法人日本循環器学会, 2003年03月01日, Circulation journal : official journal of the Japanese Circulation Society, 67, 398 - 398, 英語Xenogenic Macrophage Immunization as a Vaccine Reduces Atherosclerosis in Apolipoprotein E Knockout Mice
- LIPPINCOTT WILLIAMS & WILKINS, 2002年11月, CIRCULATION, 106(19) (19), 30 - 30, 英語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研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2002年11月, CIRCULATION, 106(19) (19), 70 - 70, 英語Supplementation of tetrahydrobiopterin inhibits atherosclerosis in apolipoprotein E-deficient mice研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2002年11月, CIRCULATION, 106(19) (19), 182 - 182, 英語Xenogenic macrophage immunization as a vaccine reduces atherosclerosis in apolipoprotein E knockout mice研究発表ペーパー・要旨（国際会議）
- 2002年08月25日, 脈管学, 42(8) (8), 493 - 498, 日本語生体内微小血管造影法の開発 : マウス末梢血管造影と冠動脈造影での冠動脈病変の評価
- 2002年05月25日, 脈管学, 42(5) (5), 291 - 296, 日本語脈管疾患の病態における内皮型NO合成酵素の作用の多様性
- 社団法人日本循環器学会, 2002年03月31日, Circulation journal : official journal of the Japanese Circulation Society, 66, 289 - 289, 英語In Vivo Mouse Coronary Angiography Using Synchrotron Radiation Microangiography
- 社団法人日本循環器学会, 2002年03月31日, Circulation journal : official journal of the Japanese Circulation Society, 66, 520 - 520, 英語A HMG-CoA Reductase Inhibitor Reduces Stroke Events and Mortality In Stroke-Prone Spontaneous Hypertensive Rats
- 社団法人日本循環器学会, 2002年03月31日, Circulation journal : official journal of the Japanese Circulation Society, 66, 411 - 411, 英語Supplement of tetrahydrobiopterin inhibits atherosclerosis in apoE-deficient mice
- 社団法人日本循環器学会, 2002年03月31日, Circulation journal : official journal of the Japanese Circulation Society, 66, 638 - 638, 英語A HMG-CoA Reductase Inhibitor Reduces Hypertensive Nephrosclerosis In Stroke Prone-SHR
- 社団法人日本循環器学会, 2002年03月31日, Circulation journal : official journal of the Japanese Circulation Society, 66, 209 - 209, 英語Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion development in apoE-deficient mice
- 現代医療社, 2002年, 現代医療, 34(4) (4), 2733 - 2738, 日本語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)
- LIPPINCOTT WILLIAMS & WILKINS, 2002年01月, CIRCULATION, 105(2) (2), E3 - E4, 英語Mouse coronary angiograph using synchrotron radiation microangiographyその他
- LIPPINCOTT WILLIAMS & WILKINS, 2001年10月, CIRCULATION, 104(17) (17), 273 - 273, 英語Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion development in ApoE-deficient mice研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 1999年11月, CIRCULATION, 100(18) (18), 114 - 114, 英語Endogeneous nitric oxide attenuates chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling: A study using endothelial nitric oxide synthase overexpressing mice研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 1999年11月, CIRCULATION, 100(18) (18), 113 - 113, 英語Resistance to endotoxin shack in transgenic mice overexpressing endothelial nitric oxide synthase研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 1999年11月, CIRCULATION, 100(18) (18), 3 - 3, 英語Nitric oxide overproduced by endothelial cells prevents vascular remodeling in the mouse carotid artery研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 1998年10月, CIRCULATION, 98(17) (17), 44 - 44, 英語Reduced relaxations to NO/cGMP-mediated vasodilators in transgenic mice overexpressing endothelial nitric oxide synthase研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 1998年10月, CIRCULATION, 98(17) (17), 4 - 5, 英語Unchanged neurohumoral regulatory factors of blood pressure in endothelial cell nitric oxide synthase-overexpressing mice研究発表ペーパー・要旨（国際会議）
- AMER HEART ASSOC, 1997年10月, CIRCULATION, 96(8) (8), 3073 - 3073, 英語Generation of transgenic mice overexpressing endothelial cell nitric oxide synthase in the vascular wall研究発表ペーパー・要旨（国際会議）
- AMER HEART ASSOC, 1997年10月, CIRCULATION, 96(8) (8), 2816 - 2816, 英語Lysophosphatidylcholine inhibits basic FGF-mediated proliferation and migration of vascular endothelial cells via the inhibition of MAP kinase activation研究発表ペーパー・要旨（国際会議）
- 分担執筆, 腸内細菌と循環器疾患, 南江堂, 2020年01月循環器疾患最新の治療2020-2021
- 分担執筆, 腸内細菌, 日本医師会, 2019年10月動脈硬化診療のすべて
- 分担執筆, 腸内細菌叢のバランス異常と疾患 循環器疾患, 羊土社, 2019年09月もっとよくわかる！ 腸内細菌叢 健康と疾患を司る”もう１つの臓器”
- 分担執筆, 腸から動脈硬化を予防する, 南山堂, 2019年03月新しい臨床を開拓するための分子循環器病学
- 分担執筆, 動脈硬化と腸内細菌, シーエムシー出版, 2015年12月, 日本語腸内細菌・口腔細菌と全身疾患学術書
- 分担執筆, 腸内細菌と動脈硬化, 中外医学社, 2013年Annual Review糖尿病・代謝・内分泌2013
- 分担執筆, 血管障害の背景 炎症, ライフサイエンス, 2007年05月, 日本語血管保護の新戦略学術書
- 分担執筆, 炎症, 日本医学出版, 2007年03月, 日本語酸化ストレスと心血管病学術書
- 分担執筆, 血管内皮, 日本医師会, 2007年, 日本語メタボリックシンドロームup to date学術書
- 分担執筆, 診断の進歩 虚血性心疾患 EPAの効果, 中外医学社, 2007年, 日本語Annual Review循環器2007学術書
- 第84回日本循環器学会学術集会, 2020年07月, 日本語心不全と腸内細菌叢
- 第60回日本神経内科学会学術大会, 2019年05月, 英語Gut microbiome and atherosclerosis[招待有り]シンポジウム・ワークショップパネル（指名）
- 第53回糖尿病のの進歩, 2019年03月, 日本語, 日本糖尿病学会, 青森, 腸内細菌と循環器疾患との関係, 国内会議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[招待有り]口頭発表（招待・特別）
- 日本農芸化学会2019年度大会, 2019年03月, 日本語, 東京農業大学 世田谷キャンパス, 国内会議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ポスター発表
- 第83回日本循環器学会学術集会, 2019年03月, 日本語, 日本循環器学会, 横浜, 国内会議The Correlation between Circulating Intermediate CD14++CD16+Monocytes and Atrial Electrical Remodeling in Atrial Fibrillation Patientsポスター発表
- 第83回日本循環器学会学術集会, 2019年03月, 日本語, 日本循環器学会, 神奈川, Gut microbiome could be therapeutic targets for prevention of cardiovascular disease, 国内会議Gut microbiome, novel therapeutic targets for preventing atherosclerotic cardiovascular diseasesシンポジウム・ワークショップパネル（公募）
- 第12回日本性差医学・医療学会学術集会, 2019年01月, 日本語, 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, 国内会議腸内細菌叢と循環器疾患〜性差からの考察を加えて〜[招待有り]口頭発表（招待・特別）
- 第22回日本心不全学会学術集会, 2018年10月, 日本語, 日本心不全学会, 東京, 腸内細菌と循環器疾患との関係, 国内会議冠動脈疾患と心不全における心臓腸管連関シンポジウム・ワークショップパネル（公募）
- 第22回日本心不全学会学術集会, 2018年10月, 英語, 日本心不全学会, 東京, We investigate the relationship between the gut microbiome and heart failure., 国内会議Gut microbiome composition and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure口頭発表（一般）
- 第2回日本循環器学会基礎研究フォーラム, 2018年09月, 日本語, 日本循環器学会, 奈良, We investigate the relationship between the gut microbiome and heart failure., 国内会議Gut microbiome composition and plasma microbial metabolites in patients with heart failureポスター発表
- 第66回日本心臓病学会, 2018年09月, 日本語, 日本心臓病学会, 大阪, Bacteroidesが動脈硬化を抑制する。, 国内会議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口頭発表（一般）
- 第2回日本循環器学会基礎研究フォーラム, 2018年09月, 英語, 日本循環器学会, 奈良, Bacteroides inhibits atherosclerosis., 国内会議Bacteroides inhibits atherosclerosis by regulating gut microbial LPS productionポスター発表
- 第50回日本動脈硬化学会, 2018年07月, 日本語, 日本動脈硬化学会, 大阪, Bacteroidesが動脈硬化を抑制する。, 国内会議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ポスター発表
- 第50回日本動脈硬化学会総会・学術集会, 2018年07月, 日本語, 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, 国内会議紫外線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口頭発表（一般）
- 第65回日本不整脈心電学会学術大会, 2018年07月, 英語, 日本不整脈心電学会, 東京, 国内会議The correlation between circulating intermediate CD14++CD16+monocytes and atrial electrical remodeling in AF patientsポスター発表
- 第22回腸内細菌学会, 2018年05月, 日本語, 腸内細菌学会, 東京, Bacteroidesが動脈硬化を抑制する。, 国内会議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口頭発表（一般）
- 第82回日本循環器学会学術集会, 2018年03月, 日本語, 日本循環器学会, 大阪, 腸内細菌と心不全との関係を調査した, 国内会議Gut microbiota and their relevant metabolites could be novel biomarkers and innovative therapeutic targets of chronic heart failureシンポジウム・ワークショップパネル（公募）
- 第82回日本循環器学会学術集会, 2018年03月, 日本語, 日本循環器学会, 大阪, 腸内細菌と心不全との関係を調査した, 国内会議Alterations of gut microbiota composition and microbiota-associated metabolites in chronic heart failure口頭発表（一般）
- Cardiovascular and metabolic week 2017, 2017年12月, 日本語, 日本血管生物医学会・日本心血管内分泌代謝学会・国際心臓研究学会日本部会, 大阪, 腸内細菌と冠動脈疾患および心不全との関係を調査した, 国内会議冠動脈疾患と心不全における腸内細菌の役割[招待有り]シンポジウム・ワークショップパネル（指名）
- The 6th International Congress on Lipid & Atherosclerosis, 2017年09月, 英語, Korean Society of Lipid and Atherosclerosis, ソウル, 韓国, 腸内細菌と炎症・免疫との関連性, 国際会議Prevention of atherosclerosis vis modulating the inflammatory process; Intestinal immunity and gut microbiota in atherosgenesis[招待有り]シンポジウム・ワークショップパネル（指名）
- 第49回日本動脈硬化学会総会・学術集会, 2017年07月, 日本語, 日本動脈硬化学会, 広島, 腸内細菌と冠動脈疾患発症との関係を調査した, 国内会議腸内細菌と動脈硬化性疾患シンポジウム・ワークショップパネル（公募）
- 第39回日本光医学・光生物学会, 2017年07月, 日本語, 日本光医学・光生物学会, 名古屋, 国内会議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口頭発表（一般）
- 第49回日本動脈硬化学会総会・学術集会, 2017年07月, 日本語, 日本動脈硬化学会, 広島, UVBが腹部大動脈瘤を抑制することを報告した, 国内会議紫外線照射による免疫制御を介した腹部大動脈瘤の新規治療法ポスター発表
- 第39回日本光医学・光生物学会, 2017年07月, 日本語, 日本光医学・光生物学会, 名古屋, 国内会議紫外線照射による動脈硬化抑制効果の検討口頭発表（一般）
- 第39回日本血栓止血学会学術集会, 2017年06月, 日本語, 日本血栓止血学会, 名古屋, 腸内細菌と冠動脈疾患発症との関係を調査した, 国内会議腸内細菌と動脈硬化・アテローム血栓症[招待有り]シンポジウム・ワークショップパネル（指名）
- 第21回腸内細菌学会, 2017年06月, 日本語, 日本ビフィズス菌センター, 神戸, 日本, 腸内細菌と冠動脈疾患発症との関係を調査した, 国内会議腸内細菌と循環器疾患[招待有り]シンポジウム・ワークショップパネル（指名）
- 第27回日本サイトメトリー学会学術集会, 2017年06月, 日本語, 日本サイトメトリー学会, 神戸, 日本, 腸内細菌と冠動脈疾患発症との関係を調査した, 国内会議腸内細菌と冠動脈疾患[招待有り]シンポジウム・ワークショップパネル（指名）
- 第17回日本NO学会学術集会, 2017年05月, 日本語, 日本NO学会, 徳島, 腸内細菌と冠動脈疾患発症との関係を調査した, 国内会議腸内細菌と循環器疾患[招待有り]シンポジウム・ワークショップパネル（指名）
- 第81回日本循環器学会学術集会, 2017年03月, 英語, 日本循環器学会, 金沢, UVB irradiation to the skin inhibits abdominal aortic aneurysm in mice, 国内会議Ultraviolet B Irradiation Inhibits the Development of Angiotensin II-Induced Abdominal Aortic Aneurysm Formation by Regulating Immuno-Inflammatory Responses口頭発表（一般）
- 第81回日本循環器学会学術集会, 2017年03月, 英語, 日本循環器学会, 金沢, 紫外線照射はマウスモデルにおいて心筋梗塞の予後を改善させる, 国内会議Ultraviolet B exposure improves survival after myocardial infarction in mice口頭発表（一般）
- 第81回日本循環器学会学術集会, 2017年03月, 日本語, 日本循環器学会, 金沢, 冠動脈疾患の残余リスクとしての腸内細菌の可能性を検討, 国内会議Gut Microbiota as Residual Risks and Novel Therapeutic Targets in Coronary Artery Diseaseシンポジウム・ワークショップパネル（公募）
- 第46回日本心脈管作動物質学会, 2017年02月, 日本語, 日本心脈管作動物質学会, 沖縄, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議腸から動脈硬化を予防する〜腸内細菌と心血管病との関連について〜[招待有り]シンポジウム・ワークショップパネル（指名）
- 第24回日本血管生物医学会学術集会, 2016年12月, 日本語, 日本血管生物医学会, 長崎, UVB irradiation to the skin inhibits abdominal aortic aneurysm in mice, 国内会議Ultraviolet B Exposure Limits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice[招待有り]シンポジウム・ワークショップパネル（指名）
- 第41回日本微小循環学会, 2016年09月, 日本語, 日本微小循環学会, 東京, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議Gut microbiota and cardiovascular disease[招待有り]シンポジウム・ワークショップパネル（指名）
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, 動脈硬化における制御性T細胞の役割ついて報告した, 国内会議動脈硬化における制御性T細胞の役割[招待有り]シンポジウム・ワークショップパネル（指名）
- 第22回日本心臓リハビリテーション学会, 2016年07月, 日本語, 日本心臓リハビリテーション学会, 東京, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議心臓病予防における腸内細菌の役割〜現状と展望〜[招待有り]シンポジウム・ワークショップパネル（指名）
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, UVBが腹部大動脈瘤を抑制することを報告した, 国内会議アンギオテンシンII誘導性マウス大動脈瘤モデルを用いた、UVB照射による大動脈瘤抑制効果の検討ポスター発表
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, 乳酸菌R037が動脈硬化をマウスモデルにおいて抑制することを報告した。, 国内会議Oral administration of the Lactic Acid Bacterium Pediococuss acidililactici attenuates atherosclerosis via inducing tolerogenic dedritic cells in miceポスター発表
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議Intestinal immunity and gut microbiota in atherogenesis口頭発表（一般）
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, 冠動脈疾患患者に特徴的な腸内細菌叢について報告した, 国内会議Dysbiosis of gut microbiota in coronary artery diesease patientsポスター発表
- 第48回日本動脈硬化学会総会・学術集会, 2016年07月, 日本語, 日本動脈硬化学会, 東京, CTLA-4 prevents atherosclerosis in mice, 国内会議Co-inhibitory molecule CTLA-4 regulates atherosclerosis by suppressing T cell and dendritic cell activation in miceポスター発表
- 日本オミックス医療学会, 2016年06月, 日本語, 日本オミックス学会, 東京, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議腸内細菌と循環器疾患[招待有り]シンポジウム・ワークショップパネル（指名）
- 第89回日本内分泌学会学術総会, 2016年04月, 日本語, 日本内分泌学会, 京都, 腸内細菌叢と冠動脈疾患との関連を報告した, 国内会議腸内細菌と動脈硬化[招待有り]シンポジウム・ワークショップパネル（指名）
- 第80回日本循環器学会学術集会, 2016年03月, 英語, 日本循環器学会, 仙台, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国内会議Ultraviolet B exposure prevents atherosclerosisポスター発表
- 第80回日本循環器学会学術集会, 2016年03月, 英語, 日本循環器学会, 仙台, CTLA-4 regulates proatherogenic immune responses through cell intrinsic and extrinsic pathways and could be an attractive therapeutic target for atherosclerosis., 国内会議Overexpression of CTLA-4 prevents atherosclerosis by suppressing T cell activation in mice口頭発表（一般）
- 第80回日本循環器学会学術集会, 2016年03月, 英語, 日本循環器学会, 仙台, Administration of lactic acid bacterium prevented atherosclerosis and could be an atractive aproach for prevention of atherclerosis., 国内会議Oral administration of the Lactic Acid Bacterium Pediococcus acidilactici attenuates atherosclerosis via inducing tolerogenic dendritic cells in miceポスター発表
- 第80回日本循環器学会学術集会, 2016年03月, 英語, 日本循環器学会, 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., 国内会議Gut microbiota could be a predictor of the risk of coronary atherosclerosis.口頭発表（一般）
- 第80回日本循環器学会学術集会, 2016年03月, 日本語, 日本循環器学会, 仙台, Gut microbiota was changed in CAD patients and could be a therapeutic target., 国内会議Gut microbiota could be a diagnostic marker or a therapeutic target of coronary artery disease.シンポジウム・ワークショップパネル（公募）
- 第23回日本血管生物医学会学術集会, 2015年12月, 日本語, 日本血管生物医学会, 神戸, Gut microbiota was changed in CAD patients and could be a therapeutic target., 国内会議腸から動脈硬化を予防する[招待有り]シンポジウム・ワークショップパネル（指名）
- 第23回日本血管生物医学会学術集会, 2015年12月, 日本語, 日本血管生物医学会, 神戸, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国内会議紫外線(UVB)照射を用いた新規動脈硬化治療法の開発口頭発表（一般）
- 第23回日本血管生物医学会学術集会, 2015年12月, 日本語, 日本血管生物医学会, 神戸, CTLA-4 regulates proatherogenic immune responses through cell intrinsic and extrinsic pathways and could be an attractive therapeutic target for atherosclerosis., 国内会議共免疫抑制分子CTLA-4による動脈硬化抑制機構の解明口頭発表（一般）
- 第23回日本血管生物医学会学術集会, 2015年12月, 日本語, 日本血管生物医学会, 神戸, A characteristic change of gut microbiota was observed in CAD patients, 国内会議冠動脈疾患患者における腸内細菌叢の特徴ポスター発表
- 第120回日本循環器学会近畿地方会, 2015年11月, 日本語, 日本循環器学会 近畿支部, 大阪, A characteristic change of gut microbiota was observed in CAD patients, 国内会議冠動脈疾患患者に特徴的な腸内細菌叢の同定口頭発表（一般）
- 第43回日本臨床免疫学会総会, 2015年10月, 日本語, 日本臨床免疫学会, 神戸, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国内会議紫外線（UVB）照射による動脈硬化抑制効果の検討ポスター発表
- 4th International Congress on Lipid Metabolism & Atherosclerosis., 2015年09月, 英語, Korean Socisty of Lipidology and Atherosclerosis, ソウル, 韓国, A characteristic change of gut microbiota was observed in CAD patients, 国際会議A possible link of gut microbiota alteration in atherosclerotic cardiovascular diseases.[招待有り]シンポジウム・ワークショップパネル（指名）
- 第47回日本動脈硬化学会総会, 2015年07月, 日本語, 日本動脈硬化学会, 仙台, Coronary artery disease was associated with a change in the composition of gut microbiota., 国内会議冠動脈疾患患者に特徴的な腸内細菌叢の変化ポスター発表
- 第19回腸内細菌学会, 2015年06月, 日本語, 日本ビフィズス菌センター, 東京, A characteristic change of gut microbiota was observed in CAD patients, 国内会議冠動脈疾患患者に特徴的な腸内細菌叢の同定口頭発表（一般）
- 第79回日本循環器学会学術集会, 2015年04月, 日本語, 日本循環器学会, 大阪, The skin and intestine could be new therapeutic targets for preventing atherosclerotic disease., 国内会議Regulatory T Cells and Tolerogenic Dendritic Cells are Critical Immunomodulators Linking the Skin and Intestinal Immune System to Atherosclerosis[招待有り]シンポジウム・ワークショップパネル（指名）
- 第79回日本循環器学会学術集会, 2015年04月, 英語, 日本循環器学会, 大阪, CTLA-4 regulates proatherogenic immune responses through cell intrinsic and extrinsic pathways and could be an attractive therapeutic target for atherosclerosis., 国内会議Proatherogenic Immune Responses are Regulated by Overexpression of a Coinhibitory Molecule CTLA-4 in Apolipoprotein E-deficient Mice口頭発表（一般）
- 第79回日本循環器学会学術集会, 2015年04月, 英語, 日本循環器学会, 大阪, Intervention to intestinal immunity or gut microbiota for prevention of atherosclerosis, 国内会議Intestinal Immunity and Gut Microbiota as Therapeutic Targets for Preventing Atherosclerotic Cardiovascular Diseases[招待有り]シンポジウム・ワークショップパネル（指名）
- 第79回日本循環器学会学術集会, 2015年04月, 英語, 日本循環器学会, 大阪, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国内会議Foxp3+ Regulatory T Cells Play a Protective Role in Angiotensin II-induced Aortic Aneurysm Formation in Mice口頭発表（一般）
- 第79回日本循環器学会学術集会, 2015年04月, 英語, 日本循環器学会, 大阪, Foxp3+ Tregs and Tr1 cells would cooperatively inhibit atherosclerotic plaque formation in hypercholesterolemic mice., 国内会議Foxp3+ Regulatory T Cells and T Regulatory Type 1 Cells Cooperatively Inhibit the Development of Atherosclerosis in Mice口頭発表（一般）
- 第79回日本循環器学会学術集会, 2015年04月, 英語, 日本循環器学会, 大阪, Coronary artery disease was associated with a change in the composition of gut microbiota., 国内会議A Characteristic Change of Gut Microbiota in Coronary Artery Diseaseポスター発表
- 第207回日本内科学会近畿地方会, 2015年03月, 日本語, 日本内科学会, 大阪, 国内会議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口頭発表（一般）
- 64th Annual Scientific Session, American College of Cardiology, 2015年03月, 英語, 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, 国際会議Circulating intermediate CD14++CD16+ monocytes increase in patients with atrial fibrillation and reflect functional remodeling of left atriumポスター発表
- 第118回日本循環器学会近畿地方会, 2014年11月, 日本語, 日本循環器学会, 大阪, 国内会議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口頭発表（一般）
- 第35回日本肥満学会, 2014年10月, 日本語, 日本肥満学会, 宮崎, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸内細菌叢への介入と腸管免疫修飾による動脈硬化予防[招待有り]シンポジウム・ワークショップパネル（指名）
- 第21回日本心血管インターベンション治療学会, 2014年10月, 日本語, 日本心血管インターベンション治療学会, 大阪, 国内会議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例口頭発表（一般）
- 第205回日本内科学会近畿地方会, 2014年09月, 日本語, 日本内科学会, 大阪, 国内会議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例口頭発表（一般）
- 第46回日本動脈硬化学会総会, 2014年07月, 日本語, 日本動脈硬化学会, 東京, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸内細菌と動脈硬化シンポジウム・ワークショップパネル（公募）
- 第35回日本循環制御医学会総会, 2014年07月, 日本語, 日本循環制御医学会, 福岡, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議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[招待有り]シンポジウム・ワークショップパネル（指名）
- 第46回日本動脈硬化学会総会, 2014年07月, 日本語, 日本動脈硬化学会, 東京, We clarified the role of regulatory T cells in human atherosclerotic disease., 国内会議Regulatory T cells and CD4+CD28null T cells in coronary artery diseaseポスター発表
- 第46回日本動脈硬化学会総会, 2014年07月, 日本語, 日本動脈硬化学会, 東京, A change of gut microbiota in coronary artery disease, 国内会議Gut microbiota modulates coronary atherogenesisポスター発表
- 第117回日本循環器学会近畿地方会, 2014年07月, 日本語, 日本循環器学会近畿支部, 大阪, 国内会議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例口頭発表（一般）
- 第56回日本老年医学会学術集会, 2014年06月, 日本語, 日本老年医学会, 福岡, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸から動脈硬化を予防する[招待有り]シンポジウム・ワークショップパネル（指名）
- The 53th Annual Conference of the Particle Therapy Co-Operative Group, 2014年06月, 英語, PTCOG 53 Hosting/Organizing Committee, Shanghai, 国際会議Particle Therapy Using Carbon Ions or Protons for Chondrosarcomas:a Single-Institution Retrospective Analysis口頭発表（一般）
- 第78回日本循環器学会学術集会, 2014年03月, 英語, 日本循環器学会, 東京, We clarified the role of regulatory T cells in human atherosclerotic disease., 国内会議The effector/ regulatory T cell ratio is reduced in coronary artery diseaseポスター発表
- 第78回日本循環器学会学術集会, 2014年03月, 日本語, 日本循環器学会, 東京, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国内会議Regulatory T Cells Play a Protective Role in Angiotensin II-Induced Aortic Aneurysm Formation口頭発表（一般）
- 第78回日本循環器学会学術集会, 2014年03月, 英語, 日本循環器学会, 東京, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国内会議Regulation of Pathogenic Inflammatory Responses via Modulating Skin Immune System for Prevention of Atherosclerosis口頭発表（一般）
- 第78回日本循環器学会学術集会, 2014年03月, 英語, 日本循環器学会, 東京, Intestine and gut bacterial flora in atherogenesis., 国内会議Intestine and gut bacterial flora in atherogenesis.[招待有り]シンポジウム・ワークショップパネル（指名）
- 第78回日本循環器学会学術集会, 2014年03月, 英語, 日本循環器学会, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., 国内会議Anti-CD3 antibody and interleukin-2 complex combination therapy inhibits atherosclerosis development by dramatically augmenting a regulatory immune responseポスター発表
- 第43回日本心血管作動物質学会, 2014年02月, 日本語, 日本心血管作動物質学会, 神戸, 動脈硬化症における制御性T細胞の役割の解明およびその制御による新規の動脈硬化治療・予防法の開発について講演した。, 国内会議免疫制御による動脈硬化性疾患予防・治療戦略[招待有り]シンポジウム・ワークショップパネル（指名）
- 第43回日本心血管作動物質学会, 2014年02月, 日本語, 日本心血管作動物質学会, 神戸, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., 国内会議抗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ポスター発表
- 第43回日本心血管作動物質学会, 2014年02月, 日本語, 日本心血管作動物質学会, 神戸, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国内会議アンジオテンシンII負荷腹部大動脈瘤マウスモデルにおける制御性T細胞の役割の検討ポスター発表
- 第34回心筋生検研究会, 2013年11月, 日本語, 心筋生検研究会, 松本, 動脈硬化症における制御性T細胞の役割の解明およびその制御による新規の動脈硬化治療・予防法の開発について講演した。, 国内会議動脈硬化性疾患予防・治療のための抗炎症戦略 -制御性T細胞誘導を介する抗動脈硬化免疫療法の試み-[招待有り]口頭発表（招待・特別）
- 第86回米国心臓学会議, 2013年11月, 英語, American heart association, Dallas, USA, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国際会議In vivo expansion of regulatory T cells attenuates aortic aneurysm formation in angiotensin II- infused apolipoprotein E-deficient mice口頭発表（一般）
- 第86回米国心臓学会議, 2013年11月, 英語, 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., 国際会議A novel combination therapy with anti-CD3 antibody and IL-2 complexes against atherosclerosis targeting effector T cells and regulatory T cellsポスター発表
- 第86回米国心臓学会議, 2013年11月, 英語, American heart association, Dallas, USA, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国際会議Activation of skin dendritic cells controls atherogensis in miceポスター発表
- 第85回米国心臓学会議, 2013年11月, 英語, 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., 国際会議Activation of regulatory T cells by ultraviolet irradiation controls atherogenesis in miceポスター発表
- 第23回日本病態生理学会, 2013年08月, 日本語, 日本病態生理学会, 東京, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸から動脈硬化を予防する[招待有り]シンポジウム・ワークショップパネル（指名）
- 第45回日本動脈硬化学会総会, 2013年07月, 日本語, 日本動脈硬化学会, 東京, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸から動脈硬化を予防する[招待有り]シンポジウム・ワークショップパネル（指名）
- 第45回日本動脈硬化学会総会, 2013年07月, 日本語, 日本動脈硬化学会, 東京, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国内会議The effects in vivo expansion of regulatory T cells on abdominal aortic aneurysm in the angiotensin II-induced murine modelポスター発表
- 第45回日本動脈硬化学会総会, 2013年07月, 日本語, 日本動脈硬化学会, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., 国内会議The balance between regulatory T cells and effector T cells is important for the control of atherosclerosisポスター発表
- 第45回日本動脈硬化学会総会, 2013年07月, 日本語, 日本動脈硬化学会, 東京, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., 国内会議Regression of atherosclerosis with anti-CD3 antibody via modulating the ratio of effector andregulatory T cells in miceポスター発表
- 第45回日本動脈硬化学会総会, 2013年07月, 日本語, 日本動脈硬化学会, 東京, Low-dose UVB irradiation to the skin reduces atherosclerosis through the modulation of skin immune system., 国内会議Activation of skin dendritic cells controls atherogensis in miceポスター発表
- 第17回腸内細菌学会, 2013年06月, 日本語, 日本ビフィズス菌センター, 東京, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議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[招待有り]シンポジウム・ワークショップパネル（指名）
- 第13回抗加齢医学会総会, 2013年06月, 日本語, 日本抗加齢医学会, 横浜, 腸管からの免疫修飾による動脈硬化予防と腸内細菌との関連を調査した研究, 国内会議腸管免疫制御による動脈硬化予防戦略[招待有り]シンポジウム・ワークショップパネル（指名）
- 日本内科学会近畿地方会, 2013年04月, 日本語, 日本内科学会, 東京, 国内会議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口頭発表（一般）
- 第35回日本造血細胞移植学会総会, 2013年03月, 日本語, 日本造血細胞移植学会, 金沢, 国内会議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ポスター発表
- 第77回日本循環器学会学術集会, 2013年03月, 英語, 日本循環器学会, 横浜, We clarified the role of regulatory T cells in the development of aortic aneurysm., 国内会議In vivo expansion of regulatory T cells attenuates aortic aneurysm formation in angiotensin II- infused apolipoprotein E-deficient miceポスター発表
- 第77回日本循環器学会学術集会, 2013年03月, 日本語, 日本循環器学会, 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 therapeutic targets for preventing atherosclerosis., 国内会議Intestine and skin could be novel therapeutic targets for preventing cardiovascular diseases.シンポジウム・ワークショップパネル（公募）
- 第77回日本循環器学会学術集会, 2013年03月, 英語, 日本循環器学会, 横浜, We clarified the role of regulatory T cells in the development of atherosclerosis., 国内会議A novel mouse model to deplete regulatory T cells uncovers their role in atherogenesis under hypercholesterolemiaポスター発表
- 第77回日本循環器学会学術集会, 2013年03月, 英語, 日本循環器学会, 横浜, Atherosclerosis is a chronic inflammatory disease and an intervention to the inflammatory process could be new therapeutic strategies for preventing atherosclerotic diseases., 国内会議A novel combination therapy with anti-CD3 antibody and IL-2 complexes against atherosclerosis targeting effector T cells and regulatory T cells口頭発表（一般）
- 第44回日本動脈硬化学会総会, 2012年07月, 日本語, 日本動脈硬化学会, 福岡, 動脈硬化は炎症性疾患と考えられており、抗炎症免疫調節療法の開発を行っている。腸管からの免疫修飾による、動脈硬化の予防法について紹介する。, 国内会議腸管免疫修飾による新規動脈硬化予防法の開発シンポジウム・ワークショップパネル（公募）
- 日本食品免疫学会第5回シンポジウム, 2012年06月, 日本語, 日本食品免疫学会, 東京, 動脈硬化は炎症性疾患と考えられており、抗炎症免疫調節療法の開発を行っている。腸管からの免疫修飾による、動脈硬化の予防法について紹介する。, 国内会議腸と皮膚からの免疫調節による新規動脈硬化予防法の開発研究[招待有り]シンポジウム・ワークショップパネル（指名）
- 第76回日本循環器学会総会・学術集会, 2012年03月, 英語, 日本循環器学会, 福岡, 国内会議The Expansion of Regulatory T Cells with IL-2/IL-2mAb Complexes Reduces the Development of Atherosclerosisポスター発表
- 第76回日本循環器学会総会・学術集会, 2012年03月, 日本語, 日本循環器学会, 福岡, 国内会議Regulation of Inflammation via Modulating Intestinal Immunity for Prevention of Atherosclerotic Cardiovascular Diseases口頭発表（一般）
- 第76回日本循環器学会総会・学術集会, 2012年03月, 英語, 日本循環器学会, 福岡, 国内会議Immunosuppressive Agent Anti-CD3 Antibody But Not Everolimus Regresses Established Atherosclerosis Althogh Both Dramatically Reduce Effector T Cells in Mice口頭発表（一般）
- 第76回日本循環器学会総会・学術集会, 2012年03月, 英語, 日本循環器学会, 福岡, 国内会議A novel ultraviolet-based phototherapy against atherosclerosis targeting regulatory T cells and skin dendritic cells[招待有り]口頭発表（招待・特別）
- The XVI International Symposium on Atherosclerosis (ISA2012), 2012年03月, 英語, 国際動脈硬化学会, シドニー, オーストラリア, 国際会議A novel ultraviolet-based phototherapy against atherosclerosis targeting regulatory T cells and skin dendritic cells口頭発表（一般）
- 第75回日本循環器学会総会・学術集会, 2011年08月, 英語, 日本循環器学会, 横浜, 国内会議Sunshine May Protect Ourself against Atherosclerosisポスター発表
- 第75回日本循環器学会総会・学術集会, 2011年08月, 日本語, 日本循環器学会, 横浜, 国内会議Intraperitoneal Injection of an Active form Vitamin D3 Decreases Atherosclerosis in Mice via Inducing Tolerogenic Dendritic Cellsポスター発表
- 第75回日本循環器学会総会・学術集会, 2011年08月, 日本語, 日本循環器学会, 横浜, 国内会議A Novel Atherosclerosis Regression Mouse Model for Investigating Its Underlying Mechanismポスター発表
- 第75回日本循環器学会総会・学術集会, 2011年08月, 英語, 日本循環器学会, 横浜, 国内会議Administration of Vasoactive Intestinal Peptide, an Immunoregulatory Neuropeptide, Reduces Atherosclerosis in Mice through Inducing Regulatory T Cellsポスター発表
- 第75回日本循環器学会総会・学術集会, 2011年08月, 英語, 日本循環器学会, 横浜, 国内会議Administration of Anti-CD3 Antibody Induces Regression of Established Atherosclerosis through Decreasing Effector T Cells But Not Increasing Regulatory T Cellsポスター発表
- 第43回日本動脈硬化学会, 2011年07月, 日本語, 日本動脈硬化学会, 札幌, 国内会議Ultraviolet irradiation to the skin prevents atherosclerosis through induction of regulatory T cellsポスター発表
- 第43回日本動脈硬化学会, 2011年07月, 日本語, 日本動脈硬化学会, 札幌, 国内会議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.[招待有り]口頭発表（招待・特別）
- 第43回日本動脈硬化学会, 2011年07月, 日本語, 日本動脈硬化学会, 札幌, 国内会議Anti-atherogenic immune therapy via modulation of the intestinal immune system. -The intestines as new therapeutic targets for preventing atherosclerosis-口頭発表（一般）
- Arteriosclerosis, Thrombosis,and Vascular Biology 2011, 2011年04月, 英語, American Heart Association, シカゴ, 米国, 国際会議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.[招待有り]口頭発表（招待・特別）
- 第75回日本循環器学会総会・学術集会, 2011年03月, 英語, 日本循環器学会, 横浜, 国内会議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ポスター発表
- 第75回日本循環器学会総会, 2011年03月, 英語, 日本循環器学会, 横浜, 国内会議Sunshine may protect ourself against atherosclerosisポスター発表
- 第75回日本循環器学会総会, 2011年03月, 日本語, 日本循環器病学会, 横浜, 国内会議Intraperitoneal injection of an active form Vitamin D3 decreases atherosclerosis in mice via inducing tolerogenic dendritic cells.ポスター発表
- 第75回日本循環器学会総会, 2011年03月, 日本語, 日本循環器学会, 横浜, 国内会議A novel atherosclerosis regression mouse model for investigating its underlying mechanismポスター発表
- 第75回日本循環器学会総会, 2011年03月, 英語, 日本循環器学会, 横浜, 国内会議Administration of Vasoactive Intestinal Peptide, an Immunoregulatory Neuropeptide, Reduces Atherosclerosis in Mice through Inducing Regulatory T Cellsポスター発表
- 第110回日本循環器学会近畿地方会, 2010年11月, 日本語, 日本循環器学会, 京都, 国内会議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口頭発表（一般）
- AHA Scientific Sessions 2010, 2010年11月, 英語, アメリカ心臓協会, シカゴ, アメリカ合衆国, 国際会議Orally Administered Eicosapentaenoic Acid Induces Rapid Regression of Atherosclerosis via Modulating the Phenotype of Dendritic Cells in LDL Receptor-deficient Mice.ポスター発表
- AHA Scientific Sessions 2010, 2010年11月, 英語, アメリカ心臓協会, シカゴ, アメリカ合衆国, 国際会議Effector T Cell Suppression Using Anti- CD3 Antibody Induces The Regression of Established Atherosclerosis in Mice口頭発表（一般）
- 第42回日本動脈硬化学会総会・学術集会, 2010年07月, 日本語, 日本動脈硬化学会, 岐阜, 国内会議動脈硬化予防のための抗炎症免疫療法口頭発表（一般）
- 第42回日本動脈硬化学会総会・学術集会, 2010年07月, 日本語, 日本動脈硬化学会, 岐阜, 国内会議Oral Anti-CD3 Antibody Treatment Induces Regulatory T Cells and Inhibits the Development of Atherosclerosis in Mice口頭発表（一般）
- 第191回日本内科学会近畿地方会学術集会, 2010年06月, 日本語, 日本内科学会近畿地方会, 京都, 国内会議MRIが診断と治療方針決定に有効であったEffusive constrictive pericarditisの1症例口頭発表（一般）
- 第107回日本内科学会講演会, 2010年04月, 日本語, 日本内科学会, 東京, 国内会議血管内皮機能の新指標テトラヒドロビオプテリン/ジヒドロビオプテリン比(BH4/BH2 ratio)の臨床応用と循環器疾患における測定意義の検討ポスター発表
- 日本循環器学会 第74回総会・学術集会, 2010年03月, 英語, 日本循環器学会, 京都, 国内会議Orally Administered Eicosapentaenoic Acid Induce Rapid Regression of Atherosclerosis via Modulating the Phenotype of Dendritic Cells in LDL Receptor-deficient Mice口頭発表（一般）
- 日本循環器学会 第74回学術集会, 2010年03月, 英語, 日本循環器学会, 京都, 国内会議Oral administration of an active form Vitamin D3 (Calcitriol) decreases atherosclerosis in mice via modulating immune cell phenotypes and functions.ポスター発表
- AHA 2009, 2009年11月, 英語, American Heart Association, フロリダ（オーランド）, アメリカ, 国際会議Oral administration of an active form Vitamin D3 (Calcitriol) decreases atherosclerosis in mice via modulating immune cell phenotypes and functions.ポスター発表
- 日本内科学会 第189回近畿地方会, 2009年09月, 日本語, 日本内科学会, 大阪, 国内会議診断に苦慮し、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例口頭発表（一般）
- 第31回日本光医学・光生物学会, 2009年07月, 日本語, 日本光医学・光生物学会, 大阪, 国内会議紫外線(UVB)照射による動脈硬化病変形成への影響口頭発表（一般）
- 第8回NO学会, 2009年05月, 日本語, 日本NO学会, 仙台, 国内会議Plasma tetrahydrobiopterin / dihydrobiopterin : A possible marker of endothelial dysfunctionポスター発表
- 第73回日本循環器学会 総会, 2009年03月, 英語, 日本循環器学会, 大阪, 国内会議Improved Metabolic Syndrome and Atherosclerosis by oral Eicosapentaenoic acid (EPA) treatment in LDLR-deficient mice.ポスター発表
- 日本循環器学会 第106回近畿地方会, 2008年11月, 日本語, 日本循環器学会, 神戸, 国内会議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口頭発表（一般）
- 第72回日本循環器学会総会・学術総会, 2008年03月, 英語, 日本循環器学会, 福岡, 国内会議Plasma pteridine level as a biomarker of cardiovascular diseasesポスター発表
- 第72回日本循環器学会総会・学術総会, 2008年03月, 英語, 日本循環器学会, 福岡, 国内会議Oral Anti-CD3 Antibody Treatment Induces CD4+LAP+ Regulatory T Cells and Ameliorates the Development of Atherosclerosis in Miceポスター発表
- 第72回日本循環器学会総会・学術総会, 2008年03月, 英語, 日本循環器学会, 福岡, 国内会議Atherosclerotic Plaque Imaging using Phase-Contrast X-ray Computed Tomography- Seeking for Clinical Application -口頭発表（一般）
- 第７9回AmericanHeartAssociationScientificSession, 2007年11月, 英語, The American Heart Association, Orland, アメリカ, 国際会議Oral Anti-CD3 Antibody Treatment Induces CD4+LAP+ Regulatory T Cells and Ameliorates the Development of Atherosclerosis in Mice口頭発表（一般）
- 第11回日本心不全学会学術集会, 2007年09月, 日本語, 日本心不全学会, 東京, 国内会議Myofilament Disarray in a Failing Heart of the MLP-deficient Mouse: Evidence from X-Ray Diffraction Study Using Synchrotron Radiationポスター発表
- 第103回日本日本循環器学会近畿地方会, 2007年06月, 日本語, 日本循環器学会, 大阪, 国内会議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口頭発表（一般）
- 第7１回日本循環器学会総会・学術集会, 2007年03月, 英語, 日本循環器学会, 神戸, 国内会議Plasma biopterin levels as a biomarker of endothlial dysfunction口頭発表（一般）
- 第7１回日本循環器学会総会・学術集会, 2007年03月, 英語, 日本循環器学会, 神戸, 国内会議Myofilament Disarray in a Heart of Murine Dilated Cardiomyopathy Model: Evidense from X-ray Diffraction Study Using Synchrotron Radiation口頭発表（一般）
- 第7１回日本循環器学会総会・学術集会, 2007年03月, 英語, 日本循環器学会, 神戸, 国内会議How to Regulate the Inflammation in Atherogenesis-Novel Vaccine Strategies for Prevention of Atheroscletosis[招待有り]口頭発表（招待・特別）
- 第7１回日本循環器学会総会・学術集会, 2007年03月, 英語, 日本循環器学会, 神戸, 国内会議Augmentation of Vascular Remodeling by Uncoupled eNOS in a Mouse Model of Diabetes Mellitus口頭発表（一般）
- 第7１回日本循環器学会総会・学術集会, 2007年03月, 英語, 日本循環器学会, 神戸, 国内会議An X-ray Diffraction Study on Mouse Cardiac Cross-Brigde Dynamics in vivo: Effects of Changing Heart Rate口頭発表（一般）
- アメリカ心臓病学会(AHA), 2006年11月, 英語, American Heart Association, シカゴ, 国際会議Augmentation of Vascular Remodeling due to Uncoupled eNOS in Diabetesポスター発表
- 第４７回日本脈管学会, 2006年10月, 日本語, 日本脈管学会, 神戸, 国内会議高血糖下では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口頭発表（一般）
- 第４７回日本脈管学会, 2006年10月, 日本語, 日本脈管学会, 神戸, 国内会議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口頭発表（一般）
- ヨーロッパ心臓病学会(ESC), 2006年09月, 英語, ヨーロッパ心臓病学会(ESC), バルセロナ, 国際会議The possible role of oxidative stress caused by uncoupled eNOS in left ventricular remodeling after myocardial infarction in ratポスター発表
- 第70回日本循環器学会総会・学術集会, 2006年03月, 英語, 日本循環器学会, 名古屋, 国内会議Mouse Cardiac Cross-Bridge Function Assessed in vivo by An X-ray Diffraction: Effects of Adrenergic beta-stimulation口頭発表（一般）
- 第７8回American Heart Association Scientific Session, 2005年11月, 英語, American Heart Association, ダラス, 国際会議Xenogenic Smooth Muscle Cell Immunization Reduces Neointimal Formation in Balloon-Injured Rabbit Carotid Arteries口頭発表（一般）
- 第７8回American Heart Association Scientific Session, 2005年11月, 英語, American Heart Association, ダラス, 国際会議An X-ray Diffraction Study on Mouse Cardiac Cross-Bridge Function in Vivo: Effects of Adrenergic Beta-stimulationポスター発表
- 日本心不全学会学術集会（第9回）, 2005年10月, 日本語, 日本心不全学会, 下関, 国内会議An X-ray Diffraction Study on Mouse Cardiac Cross-Bridge Function in vivo: Effects of Adrenergic beta-stimulation口頭発表（一般）
- International Symposium on Atherosclerosis 2005, 2005年06月, 英語, ローマ, 国際会議Angiotensin II Type 1 Receptor Blocker, Telmisartan Suppresses Superoxide Production and Atherosclerotic Lesion Formation in Apolipoprotein E-deficient Miceポスター発表
- American College of Cardiology Annual Scientific Session 2005, 2005年03月, 英語, American College of Cardiology, オーランド, 国際会議In Vivo Evaluation of X-ray Diffraction from the Left Ventricular Wall of Mouse Heartsポスター発表
- 第68回日本循環器学会総会・学術集会, 2004年03月, 英語, 日本循環器学会, 東京, 国内会議Overexpression of endothelial nitric oxide synthase accelerates vascular remodeling in apoE-deficient miceポスター発表
- 第９回放射光医学研究会, 2004年01月, 日本語, 放射光医学研究会, 東京, 国内会議循環器疾患における放射光微小血管造影の応用口頭発表（一般）
- 第１３回国際動脈硬化学会サテライトシンポジウム, 2003年10月, 英語, 日本動脈硬化学会, 神戸, 国際会議Xenogenic Smooth Muscle Cell Immunization as a Vaccine Reduces Neointimal Formation in Balloon-Injured Rabbit Carotid Arteries口頭発表（一般）
- 第35回日本動脈硬化学会, 2003年09月, 日本語, 日本動脈硬化学会, 京都, 国内会議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ポスター発表
- 第3回日本NO学会, 2003年05月, 日本語, 日本NO学会, 東京, 国内会議経口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口頭発表（一般）
■ 共同研究・競争的資金等の研究課題
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2024年04月01日 - 2027年03月31日動脈硬化巣のシングルセル解析とゲノム統合解析による病態解明と新規疾患予防法の開発
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2024年04月01日 - 2027年03月31日腹部大動脈瘤への新たな免疫治療開発
- 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, 2023年04月01日 - 2026年03月31日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。
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2023年04月01日 - 2026年03月31日動脈硬化性疾患シングルセルアトラスの作成とゲノム統合解析による発症メカニズム解明本研究の目的は、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。
- 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, 2022年04月 - 2025年03月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
- 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, 2022年04月 - 2025年03月大動脈解離の発生と進展に好中球が与える影響の検討
- 日本学術振興会, 科学研究費助成事業, 挑戦的研究(萌芽), 神戸大学, 2022年06月30日 - 2024年03月31日腸内細菌制御により運動と同等の効果を褐色脂肪組織に与える研究本研究の目的は、運動と同等効果を持つ腸内細菌を探索し、肥満症治療の可能性を検証する事である。『運動』にて増加する腸内細菌の特定のために、肥満モデルマウスにトレッドミル運動負荷を行ったが、本実験では運動が肥満に影響せず、運動模倣菌を絞り込むことはできなかった。高脂肪食負荷による肥満モデルマウスにBacteroides 菌を、経口投与すると、肥満を抑制し、褐色脂肪細胞の分枝鎖アミノ酸代謝を改善し、運動で起きる熱産生を再現している可能性が示された。 ヒトでやせ・肥満と腸内細菌叢との関係を再度調査し、肥満だけでなく反対の高齢者のやせの問題との関連性を調査することで、次につながる研究基盤を確立させた。
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 国立研究開発法人国立長寿医療研究センター, 2020年04月 - 2023年03月腸内細菌が認知機能に与えるインパクトの解明：認知症予防を目指した臨床研究近年、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。
- 日本学術振興会, 科学研究費助成事業, 挑戦的研究(萌芽), 神戸大学, 2020年07月 - 2022年03月腸内細菌の外膜小胞を利用した疾患治療法の開発研究本研究の目的は、腸内細菌の外膜小胞(Outer membrane vesicles; OMVs)を介する生体作用を解明して、疾患治療への応用の可能性を検証することである。OMVsは、細菌が分泌する20～250nm程度の大きさの脂質二重膜構造を持つ球状の小胞で、リポ多糖LPSを含む種々の菌体成分や各細菌のタンパクや核酸が含まれる。 腸内細菌から産生されるOMVsの単離に成功した。OMVsにはLPSが含まれており、菌固有のLPS活性の差を反映する結果が得られ、菌に特徴のあるOMVsが産生されることが確認できた。腸管から生体内・血中への移行を調査したが、移行する可能性は低いという結果となった。
- 学術研究助成基金助成金, 基盤研究(B), 2019年04月 - 2022年03月, 研究代表者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競争的資金
- 日本医療研究開発機構, 革新的先端研究開発支援事業, 2018年10月 - 2022年03月, 研究代表者ヒト腸内細菌Bacteroides２菌種の抗炎症作用機序の解明と慢性炎症性疾患治療への応用競争的資金
- 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, 2017年04月 - 2020年03月冠動脈疾患患者での腸内細菌叢調査を行い、バクテロイデス ブルガトウスとバクテロイデス ドレイの２種類の菌種が、コントロール患者に比較して減少していることを見出した。この菌を培養して、動脈硬化マウスに経口で投与すると、動脈硬化が抑制されることがわかり、その機序としては抗炎症作用を示した。以上の結果を踏まえて、このバクテロイデス２菌種は、人においても動脈硬化を予防している可能性があり、本菌を腸内細菌微生物製剤としての開発研究を行なっている。心不全患者でも同様の取り組みを実施中であり、将来の腸内細菌を変化させる新規治療法の開発につなげたい。競争的資金
- 学術研究助成基金助成金／基盤研究(C), 2016年04月 - 2019年03月, 研究代表者競争的資金
- 科学研究費補助金／基盤研究(C), 2012年04月 - 2015年03月, 研究代表者競争的資金
- 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, 2009年 - 2011年急性冠症候群の原因となる動脈硬化不安定粥腫の診断法と治療法の開発研究を進めてきた。臨床研究においては、光干渉断層映像法(OCT)を用いての冠動脈ステントの経時的観察や、ステント内血栓に関した研究、そして動脈硬化プラークの薬剤使用による安定化の研究を行った。基礎研究では、抗炎症免疫療法の成果をマウス動脈硬化モデルにおいて証明し、新規治療法の開発研究を行い論文に報告した。これらの研究を、融合させることで、将来臨床で使用できる新たな診断法や治療法の開発につながる研究を進めた。 粥腫破綻検出のためのバイオマーカーの検索に関しては、現状では実際のマーカーとして有用な物質を特定するまでには至っていない。競争的資金
- 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, 2007年 - 2008年, 研究代表者放射光を利用して、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。競争的資金
研究シーズ
■ 研究シーズ- シングルセル解析シーズカテゴリ：ライフサイエンス研究キーワード：シングルセルRNAシークエンス, 心血管疾患, 炎症・免疫細胞研究の背景と目的：シングルセル解析により、疾患の病変部の一細胞ごとの詳細な遺伝子発現情報が得られるようになり、疾患の病態解析に関しての新たな時代が訪れている。研究内容：冠動脈疾患（急性心筋梗塞・狭心症）の病変部のサンプルを用いて、動脈硬化局所に存在する免疫細胞を同定・分類することで、病態による差異を明らかにして報告した。 大動脈瘤・大動脈解離・大動脈弁狭窄症などの病変部の、シングルセル解析を進めており、心血管疾患の病態に関する新たなエビデンスを見出して、そこから新たな治療法・予防法を提案することを目指して研究を進めている。期待される効果や応用分野：治療法・予防法を提供できていない心血管疾患に対しての、新規治療標的の提案と、新規介入方法の開発。関係する業績：Emoto T et al. Single Cell RNA Seq Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome. Circulation. 2022; 145: 1434-36.
- 腸内細菌と循環器疾患との関連調査研究シーズカテゴリ：ライフサイエンス研究キーワード：腸内細菌, 冠動脈疾患, 心不全, 微生物製剤研究の背景と目的： 腸内細菌は、宿主の「免疫」「代謝」に影響を与え、健康の維持や疾患の発症にも関連することが報告されている。本研究の目的は、動脈硬化をはじめとする生活習慣病、ならびに心臓疾患と腸内細菌叢との関連を明らかにし、将来的に腸内細菌やその代謝物に介入する、循環器疾患の予防法を開発することである。研究内容： すでに、冠動脈疾患・心不全・心房細動患者の糞便中の腸内細菌叢の調査を行い、それらの循環器疾患に特徴的な腸内細菌叢の特徴を明らかにしている。臨床研究から得られた知見を、動物実験にて検証し、動脈硬化予防菌の同定も行い、その菌株を用いた微生物製剤の開発研究を実施している。
期待される効果や応用分野：腸内細菌微生物製剤の開発研究 腸内細菌を変更する、疾患予防法の開発関係する業績：Yoshida N, Emoto T, Yamashita T, et al. Bacteroides vulgatus and Bacteroides dorei reduce gut microbial lipopolysachharide production and inhibit atherosclerosis. Circulation. 2018; 138: 2486-98.
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