m6A demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3
Ri-Feng Gao,
Kun Yang,
Ya-Nan Qu,
Xiang Wei,
Jia-Ran Shi,
Chun-Yu Lv,
Yong-Chao Zhao,
Xiao-Lei Sun,
Ying-Jia Xu,
Yi-Qing Yang
Affiliations
Ri-Feng Gao
Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
Kun Yang
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China
Ya-Nan Qu
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China
Xiang Wei
Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
Jia-Ran Shi
Department of Cardiology, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
Chun-Yu Lv
Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 200240, China
Yong-Chao Zhao
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China
Xiao-Lei Sun
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China
Ying-Jia Xu
Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
Yi-Qing Yang
Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China; Department of Cardiovascular Research Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 518036, China; Department of Central Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China; Corresponding author
Summary: The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC−Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.
