2022 Fiscal Year Final Research Report

Influence of non-vascular cells in accelerated coronary aging in diabetes

Research Project

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Project/Area Number	19H03405
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 48020:Physiology-related
Research Institution	National Cardiovascular Center Research Institute
Principal Investigator	Pearson James 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (30261390)
Co-Investigator(Kenkyū-buntansha)	土持裕胤国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60379948) 曽野部崇国立研究開発法人国立循環器病研究センター, 研究所, 客員研究員 (70548289) 岩田裕子国立研究開発法人国立循環器病研究センター, 研究所, 非常勤研究員 (80171908) 杜成坤国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (90590646)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	coronary circulation / diabetes / senescence / inflammation / oxidative stress / nitric oxide
Outline of Final Research Achievements	Diabetes accelerates vascular ageing when excess oxidants exceed antioxidant capacity, vascular dysfunction and vessel rarefaction. We tested whether Nox2 contributes to coronary dysfunction in diet induced early-stage diabetes induced by high fat diet (HFD) and increased salt intake in mice treated with and without apocynin. Synchrotron microangiography revealed that the coronary capacity to produce NO (nitric oxide) was diminished by insulin resistance, suggesting Nox2 overactivation in insulin resistance reduces NO bioavailability. In SAMP8 mice glycolysis was inhibited and abnormal purine metabolism increased xanthine oxidase activation on HFD leading to microvascular dysfunction. Mice developed mild coronary dysfunction due to elevated oxidants, metabolic inflexibility and mitochondrial dysfunction. We conclude that insulin resistance greatly increases endothelin production through Nox2 to reduce NO bioavailability. iNOS upregulation promoted p53 activation in senescent mice.
Free Research Field	循環器生理学
Academic Significance and Societal Importance of the Research Achievements	我々の研究は、マウスにおいて優れたイメージング技術により、カロリー過多や塩分多量摂取などの食生活の乱れによる生活習慣病が、心臓の微小血管の早期老化を引き起こし、運動やストレス時に心臓の機能を低下させることを明らかにした。また、運動がこの血管機能障害を改善することを示し、治療のターゲットを特定した。