FOXO3a-dependent PARKIN negatively regulates cardiac hypertrophy by restoring mitophagy

Cell & Bioscience

Research

Jun-Li Yang¹  Hai-Xiong Wang²  Jia-Lei Li³  Lin Zuo³  Ji-Min Cao³  Jin Wang³  Teng Sun³  Yu Han³  Xiang-Ying Jiao³  Jian-Xun Wang⁴ 

[1] Computer teaching department, Shanxi Medical University, Taiyuan, China;Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China;Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, and the Department of Physiology, Shanxi Medical University, Taiyuan, China;School of Basic Medical Sciences, Qingdao University, Qingdao, China;

关键词: PARKIN;    FOXO3a;    Mitophagy;    Cardiac hypertrophy;   

DOI  :  10.1186/s13578-022-00935-y

 received in 2022-07-13, accepted in 2022-12-04,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundSustained cardiac hypertrophy often develops maladaptive myocardial remodeling, and eventually progresses to heart failure and sudden death. Therefore, maladaptive hypertrophy is considered as a critical therapeutic target for many heart diseases. Mitophagy, a crucial mechanism in mitochondria quality control and cellular homeostasis, has been implicated in diverse cardiac disorders such as myocardial infarction, diabetic cardiomyopathy, cardiac hypertrophy and heart failure. However, what role mitophagy plays in heart diseases remains an enigma. PARKIN functions as an E3 ubiquitin protein ligase and mediates mitophagy cascades. It is still unclear whether PARKIN participates in the regulation of cardiac hypertrophy.ResultsPARKIN was downregulated in cardiomyocytes and hearts under hypertrophic stress. Enforced expression of PARKIN inhibited Ang II-induced cardiomyocyte hypertrophy. Compared to wide-type mice with Ang II-induced cardiac hypertrophy, Parkin transgenic mice subjected to Ang II administration showed attenuated cardiac hypertrophy and improved cardiac function. In addition, mitophagy machinery was impaired in response to Ang II, which was rescued by overexpression of PARKIN. PARKIN exerted the anti-hypertrophy effect through restoring mitophagy. In further exploring the underlying mechanisms, we found that PARKIN was transcriptionally activated by FOXO3a. FOXO3a promoted mitophagy and suppressed cardiac hypertrophy by targeting Parkin.ConclusionsThe present study reveals a novel cardiac hypertrophy regulating model composed of FOXO3a, PARKIN and mitophagy program. Modulation of their levels may provide a new approach for preventing cardiac hypertrophy and heart failure.Graphical Abstract

【 授权许可】

CC BY   
© The Author(s) 2022

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