m 6 A demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3.
| Autor: | Gao RF; Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China., Yang K; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China., Qu YN; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China., Wei X; Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China., Shi JR; Department of Cardiology, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China., Lv CY; 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., Zhao YC; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China., Sun XL; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200232, China., Xu YJ; Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China., Yang YQ; 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. |
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| Jazyk: | angličtina |
| Zdroj: | IScience [iScience] 2023 Feb 16; Vol. 26 (3), pp. 106215. Date of Electronic Publication: 2023 Feb 16 (Print Publication: 2023). |
| DOI: | 10.1016/j.isci.2023.106215 |
| Abstrakt: | The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m 6 A) plays an essential role in numerous biological processes. However, the roles of m 6 A and m 6 A 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 (ALKBH5 flox/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 m 6 A-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. Competing Interests: Authors declare that they have no competing interests. (© 2023 The Authors.) |
| Databáze: | MEDLINE |
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