Endoplasmic reticulum selective autophagy alleviates chronic heart failure

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08399
• 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: Tokyo Medical and Dental University
• Principal Investigator: MAEJIMA YASUHIRO 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (40401393)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: がん治療関連心筋障害 / アントラサイクリン系抗がん剤 / 慢性心不全 / 小胞体ストレス / 小胞体選択的オートファジー

Outline of Final Research Achievements

Administration of Doxorubicin (Dox) induces progressive and dose-related cardiac damage through several cytotoxic mechanisms, including endoplasmic reticulum (ER) stress. We aimed to clarify whether ER-selective autophagy machinery (ER-phagy) serves as an alternative system to protect cardiomyocytes from ER stress caused by anthracycline drugs. Dox-induced cardiomyopathy models of ER-phagy reporter mice showed marked activation of ER-phagy in the myocardium compared to those of saline-treated mice. Dox enhanced the expression of CCPG1 in H9c2 cells and ablation of CCPG1 in H9c2 cells resulted in the reduced ER-phagy activity, accumulation of pro-apoptotic proteins and deterioration of cell survival against Dox administration. CCPG1-hypomorphic mice developed more severe deterioration in systolic function in response to Dox compared to wild-type mice.
Our findings highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究で見いだすことのできたERファジーの制御異常による心不全の発症および病状進展を引き起こす分子機序の解明は、難治性疾患である慢性心不全の治療のみにとどまらず、動脈硬化症、神経変性疾患、悪性腫瘍などERストレスが重要な役割を果たしていると考えられている疾患全般の治療に応用可能な治療法の開発の端緒になり得る重要な知見であると考える。