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

iScience (Mar 2023)

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

Journal volume & issue: Vol. 26, no. 3
p. 106215

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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