ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity
Wu, Xiaoting; Wang, Lijun; Wang, Kai; Li, Jin; Chen, Rui; Wu, Xiaodong; Ni, Gehui; Liu, Chang; Das, Saumya; Sluijter, Joost P.G.; Li, Xinli; Xiao, Junjie
(2022) Molecular Therapy, volume 30, issue 1, pp. 400 - 414
(Article)
Abstract
Exercise training benefits the heart. The knowledge of post-transcription regulation, especially RNA editing, in hearts remain rare. ADAR2 is an enzyme that edits adenosine to inosine nucleotides in double-stranded RNA, and RNA editing is associated with many human diseases. We found that ADAR2 was upregulated in hearts during exercise training.
... read more
AAV9-mediated cardiac-specific ADAR2 overexpression attenuated acute myocardial infarction (AMI), MI remodeling, and doxorubicin (DOX)-induced cardiotoxicity. In vitro, overexpression of ADAR2 inhibited DOX-induced cardiomyocyte (CM) apoptosis. but it could also induce neonatal rat CM proliferation. Mechanistically, ADAR2 could regulate the abundance of mature miR-34a in CMs. Regulations of miR-34a or its target genes (Sirt1, Cyclin D1, and Bcl2) could affect the pro-proliferation and anti-apoptosis effects of ADAR2 on CMs. These data demonstrated that exercise-induced ADAR2 protects the heart from MI and DOX-induced cardiotoxicity. Our work suggests that ADAR2 overexpression or a post-transcriptional associated RNA editing via ADAR2 may be a promising therapeutic strategy for heart diseases.
show less
Download/Full Text
Keywords: ADAR2, doxorubicin-induced cardiotoxicity, exercise, myocardial infarction, RNA editing, Drug Discovery, Genetics, Molecular Medicine, Molecular Biology, Pharmacology, Journal Article
ISSN: 1525-0016
Publisher: Nature Publishing Group
Note: Funding Information: This work was supported by grants from the National Key Research and Development Project ( 2018YFE0113500 to J.X.), the National Natural Science Foundation of China ( 81900359 to J.L.; 81730106 and 81670347 to X.L.; 81800358 to L.W.; and 82020108002 and 81911540486 to J.X.), the Innovation Program of Shanghai Municipal Education Commission ( 2017-01-07-00-09-E00042 to J.X.), the Science and Technology Commission of Shanghai Municipality ( 20DZ2255400 and 18410722200 to J.X.), the Shanghai Sailing Program ( 19YF1416400 to J.L.), the “Dawn” Program of Shanghai Education Commission ( 19SG34 to J.X.), and the Natural Science Foundation of Shanghai ( 19ZR1474100 to L.W.). X.L. is an Associate Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine. J.P.S. is supported by the European Research Council (ERC) ERC-2016-COG EVICARE (No. 725229). Publisher Copyright: © 2021 The American Society of Gene and Cell Therapy
(Peer reviewed)