The role of sirt7 in the cardiac ischemia-reperfusion injury

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08561
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kumamoto University
• Principal Investigator: Araki Satoshi 熊本大学, 地域医療・総合診療実践学寄付講座, 特任准教授 (20706717)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: sirt7 / 心筋虚血再灌流障害 / 心筋梗塞 / 酸化ストレス

Outline of Final Research Achievements

Sirt7 is one of the sirtuin family. The expression of cardiac Sirt7 expression was decreased in response to ischemia-reperfusion injury (IR injury). We created ischemia-reperfusion model in Sirt7 KO mice and WT mice. There was no difference in the area at risk (AAR). However, the infarct area/AAR were significantly decreased in Sirt7 KO mice compared with WT mice. In vitro experiments, Sirt7 knockdown in rat neonatal cardiomyocyte attenuated hypoxia-reoxygenation induced cell apoptosis. Sirt7 knockdown increased antioxidative factors after hypoxia/reoxygenation. NRF2 knockdown abolished Sirt7 knockdown-induced HO-1. NRF2 transcriptional activity was increased by Sirt7 siRNA treatment. CHIP assay revealed that knockdown of Sirt7 increased NRF2 biding at enhancer element of HO-1 promoter lesion. Sirt7 was interacted with not NRF2 but MafG. We also found that Sirt7 deacetylated MafG.
Lack of Sirt7 attenuates ischemia-reperfusion injury by modulating NRF2 activity.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

加齢関連疾患である心筋梗塞の急性期死亡率は、早期の再灌流療法や集中治療室での管理により年々低下傾向である。しかし冠動脈の血流再開時に引き起こされる虚血再灌流障害に対する有効な治療法がないため、その後に心不全を発症する患者が増加しており新たな虚血再灌流療法の開発が喫緊の課題である。本申請では心筋虚血再灌流障害においてSirt7の欠如はMafGを介したNRF2の転写活性を更新することにより、酸化ストレス抑制因子を増加させることを見出した。この結果は、心筋虚血再灌流障害においてSirt7が新たな治療ターゲットとなりうる可能性を示唆するものである。