慶應義塾研究者情報データベース

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• Sipa1 Drives a Maladaptive Fibroblast-Myeloid Axis After Myocardial Infarction

  Ko S., Liu X., Taniguchi Y., Ichihara G., Komuro J., Yamakawa H., Shirakawa K., Hashimoto H., Katsumata Y., Endo J., Hattori M., Minato N., Sano M., Anzai A., Ieda M.

  Circulation Research 137 （ 4 ） 533 - 547 2025年08月

  ISSN  00097330

  　概要を見る

  BACKGROUND: Sipa1 (signal-induced proliferation-associated gene 1) is known as a specific Rap1 (Ras-related protein 1) GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound-healing response after myocardial infarction (MI) remains unexplored. METHODS: To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both Sipa1knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast–derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro. RESULTS: Mice deficient in Sipa1 exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6C (lymphocyte antigen 6 complex, locus C)^high monocytes and CCR (C-C chemokine receptor) 2⁺ macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast–specific Sipa1 conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL (C-C chemokine ligand) 2, CCL7, and GM-CSF (granulocyte/ macrophage colony-stimulating factor) in the cardiac fibroblasts early after MI via a noncanonical RasGRP2 (Ras guanine nucleotide-releasing protein 2)-Ras-JNK (cellular Jun N-terminal kinase) signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages. CONCLUSIONS: These results identify a previously unknown fibroblast-myeloid axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound-healing response, thereby preventing the development of chronic ischemic heart failure. GRAPHIC ABSTRACT: A graphic abstract is available for this article.

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• Efficacy and Long-term Mortality After Balloon Pulmonary Angioplasty in Older Patients With Chronic Thromboembolic Pulmonary Hypertension

  Shinya Y., Kimura M., Momoi M., Hiraide T., Anzai A., Hayashida K., Kohno T., Ieda M.

  Canadian Journal of Cardiology 41 （ 8 ） 1469 - 1476 2025年08月

  ISSN  0828282X

  　概要を見る

  Background: Balloon pulmonary angioplasty (BPA) has shown short-term safety and efficacy for treating chronic thromboembolic pulmonary hypertension (CTEPH). However, it remains unclear whether these effects, as well as long-term mortality after BPA, differ depending on patient age. We investigated the safety, short-term efficacy (hemodynamics, functional capacity, and respiratory function), and long-term mortality of BPA treatment in both younger and older patients with CTEPH. Methods: We enrolled 157 consecutive patients with CTEPH who underwent BPA at a university hospital. They were divided into 2 age groups: older (≥ 75 years, n = 39) and younger (< 75 years, n = 118). Hemodynamics, functional capacity, and respiratory function were evaluated at baseline, 1 week, 6 months, and 1 year post-BPA. Procedure-related complications, all-cause mortality, and cause of mortality were assessed during hospitalization for BPA and throughout the follow-up period (median duration 5.7 years). Results: BPA improved the mean pulmonary artery pressure, pulmonary vascular resistance, 6-minute walking distance, and pulmonary diffusion capacity in both age groups. There was no all-cause mortality or use of extracorporeal membrane oxygenation during hospitalization in either group; however, the rates of noninvasive positive pressure ventilation use and intraoperative hemosputum/hemoptysis were higher in the older group. All-cause mortality was higher in the older group during the follow-up period, but all cases were unrelated to pulmonary hypertension (PH). Conclusions: BPA was effective for improving hemodynamics, functional capacity, and respiratory parameters without critical complications, regardless of patient age. The older patients in our cohort had a higher mortality rate that was unrelated to PH.

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• Social Bonds Retain Oxytocin-Mediated Brain-Liver Axis to Retard Atherosclerosis

  Ko S., Anzai A., Liu X., Kinouchi K., Yamanoi K., Torimitsu T., Ichihara G., Kitakata H., Shirakawa K., Katsumata Y., Endo J., Hayashi K., Yoshida M., Nishimori K., Tanaka K.F., Onaka T., Sano M., Ieda M.

  Circulation Research 136 （ 1 ） 78 - 90 2025年01月

  ISSN  00097330

  　概要を見る

  BACKGROUNDS: Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. METHODS: To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed Apoe^−/− mouse siblings were randomly assigned to either individual or grouped housing for 12 weeks. Histological, flow cytometric, biochemical, gene, and protein analyses were performed to assess atherosclerotic lesions, systemic metabolism, inflammation, and stress response. The effects of oxytocin on hepatocytes and subsequent cardiometabolic and cardiovascular function were investigated by in vivo and in vitro approaches. RESULTS: Apoe^−/− mice housed individually developed larger vulnerable atherosclerotic lesions by disrupted lipid metabolism compared with those of mice in regular group housing, irrespective of body weight, eating behavior, feeding conditions, sympathetic nervous activity, glucocorticoid response, or systemic inflammation. Mechanistically, the chronic isolation reduced the hypothalamic production of oxytocin, which controls bile acid production and LPL (lipoprotein lipase) activity through the peripheral OXTR (oxytocin receptor) in hepatocytes, whose downstream targets include Cyp7a1, Angptl4, and Angptl8. While hepatocyte-specific OXTR-null mice and mice receiving adeno-associated virus targeting OXTR on hepatocytes led to severe dyslipidemia and aggravated atherosclerosis, oral oxytocin supplementation to socially isolated mice, but not to hepatocyte-specific OXTR conditional knockout mice, improved lipid profiles and retarded atherosclerosis development. CONCLUSIONS: These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression.

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• Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension

  Momoi M., Katsumata Y., Kunimoto H., Inami T., Miya F., Anzai A., Goto S., Miura A., Shinya Y., Hiraide T., Shirakawa K., Endo J., Fukuda K., Ieda M., Kosaki K., Nakajima H., Kataoka M.

  Journal of the American Heart Association 13 （ 23 ）  2024年12月

  　概要を見る

  BACKGROUND: The cause of chronic thromboembolic pulmonary hypertension (CTEPH) remains largely unknown. Recently, clonal hematopoiesis (CH) has been reported to be associated with cardiovascular and thromboembolic diseases. Here, we investigated the prevalence and clinical impact of CH in patients with CTEPH. METHODS AND RESULTS: Whole-exome sequencing and deep-panel sequencing were performed in 214 patients with CTEPH. Clinical data before and after treatment were compared between patients with and without CH. RNA sequencing and serum analysis were performed to explore the pathogenesis that CH contributes to CTEPH. Among the enrolled patients, 20.1%, notably 44.4% who were 80 to 89 years old, had variants in CH-associated genes. In regard to clinical impact, B-type natriuretic peptide levels and home oxygen therapy rate were significantly higher, and 6-minute walk distance was significantly shorter after treatment in patients with CH than in those without CH. Moreover, novel clot reformation in the pulmonary artery despite the use of anticoagulants and additional angioplasty events after treatment completion were more frequent in patients with CH. RNA sequencing analysis revealed that blood coagulation and neutrophil extracellular trap formation pathways were enriched in patients with CH. Additionally, serum citrullinated histone H3 levels were higher in patients with CH than those without CH. These results were consistent in the subgroup of patients who did not have the history of hematological disorders. CONCLUSIONS: The findings in this study raise the possibility that CH will induce a more prothrombotic state through neutrophil activation and neutrophil extracellular trap formation, contributing to pathogenesis and poor treatment response in patients with CTEPH.

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• A Novel Method for Acquired Sex Chromosome Mosaicism

  Tsuchiya J., Maki Y., Ayano M., Kikuchi T., Watanabe Y., Ohtake K., Fujita R., Hayashi M., Yamamoto J., Wang Y., Anzai A., Kubo T., Sano S.

  Advanced Biology 8 （ 7 ）  2024年07月

  　概要を見る

  The phenomenon of sex chromosome loss from hematopoietic cells is an emerging indicator of biological aging. While many methods to detect this loss have been developed, enhancing the field, these existing methods often suffer from being labor-intensive, expensive, and not sufficiently sensitive. To bridge this gap, a novel and more efficient technique is developed, named the SinChro assay. This method employs multiplexed single-cell droplet PCR, designed to detect cells with sex chromosome loss at single-cell resolution. Through the SinChro assay, the age-dependent increase in Y chromosome loss in male blood is successfully mapped. The age-dependent loss of the X chromosome in female blood is also identified, a finding that has been challenging with existing methods. The advent of the SinChro assay marks a significant breakthrough in the study of age-related sex mosaicism. Its utility extends beyond blood analysis, applicable to a variety of tissues, and it holds the potential to deepen the understanding of biological aging and related diseases.

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• 心筋梗塞後の炎症・修復を制御する新たなメカニズムの解明

  安西, 淳

  学事振興資金研究成果実績報告書 （慶應義塾大学）  2022年

• 新規心臓線維芽細胞サブセットの機能解析と心筋梗塞後心不全の新たな治療戦略の開発

  安西, 淳

  福澤諭吉記念慶應義塾学事振興基金事業報告集 （福澤基金運営委員会）  2022年

• 心外膜脂肪に潜む免疫細胞を介した心筋梗塞後心不全における炎症進展機序の解明

  安西, 淳

  科学研究費補助金研究成果報告書 2021年

• 心筋梗塞後の炎症・修復を制御する新たなメカニズムの解明

  安西, 淳

  学事振興資金研究成果実績報告書 （慶應義塾大学）  2021年

• 心筋梗塞後の炎症・修復を制御する新たなメカニズムの解明

  安西, 淳

  学事振興資金研究成果実績報告書 （慶應義塾大学）  2020年

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競争的研究費の研究課題 【 表示 ／ 非表示 】

競争的研究費の研究課題 【 表示 ／ 非表示 】

• 心筋梗塞後の炎症と修復を制御する新規心臓線維芽細胞サブセットの探索

  2022年04月

  -

  2025年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 安西 淳, 基盤研究(C), 補助金,  研究代表者

• 心外膜脂肪に潜む免疫細胞を介した心筋梗塞後心不全における炎症進展機序の解明

  2018年04月

  -

  2021年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 安西　淳, 基盤研究(C), 補助金,  研究代表者

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• 薬物治療学２

  2024年度

• フィジカルアセスメント

  2021年度

• 慢性期病態学各論

  2021年度

• クリニカルエンジニアリングと医療安全管理

  2021年度

• フィジカルアセスメント

  2020年度

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