Elucidation of novel molecular mechanisms of the treatment strategy for heart failure by inactivating the DNA damage response

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08560
• 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: Miyata Keishi 熊本大学, 大学院生命科学研究部(医), 客員教授 (50398228)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 心不全 / DNA損傷応答

Outline of Final Research Achievements

Recently, cardiomyocytes that have developed heart failure show not only accumulation of fragmented DNA but also DNA damage response (DDR) activation is observed, and inflammatory cytokines induced by DDR exacerbate the development of heart failure. Although it has been clarified that DDR activation of cardiomyocytes plays an important role in the development of heart failure pathology, the detailed molecular mechanism that regulates DDR activation in cardiomyocytes is not fully elucidated. In this study, the analysis of heart failure model mice using DDR-related gene-modified mice revealed that reducing the expression of Hint1 in cardiomyocytes suppresses DDR activation in the development of heart failure and has a cardioprotective effect. Furthermore, reducing Hint1 expression was found to suppress the cardiotoxicity of adriamycin caused by DDR.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、依然として予後不良の疾患である心不全に対してDDR活性化抑制という新たな観点からの予防や新規治療法開発に繋がる可能性が期待される。さらに、近年、高齢化によって循環器疾患とがんを合併する患者が多く認められ、化学療法の進歩によりがんの治療率は格段に向上しているが、それに伴って薬剤による心毒性という副作用が問題となっている。本研究の成果はDDR活性化が原因とされるアドリアマイシンの心毒性の軽減にも繋がる可能性がある。