ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity

Xiaoting Wu; Lijun Wang; Kai Wang; Jin Li; Rui Chen; Xiaodong Wu; Gehui Ni; Chang Liu; Saumya Das; Joost P G Sluijter; Xinli Li; Junjie Xiao

doi:10.1016/j.ymthe.2021.07.004

ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity

Mol Ther. 2022 Jan 5;30(1):400-414. doi: 10.1016/j.ymthe.2021.07.004. Epub 2021 Jul 16.

Authors

Xiaoting Wu¹, Lijun Wang², Kai Wang¹, Jin Li³, Rui Chen³, Xiaodong Wu¹, Gehui Ni¹, Chang Liu³, Saumya Das⁴, Joost P G Sluijter⁵, Xinli Li⁶, Junjie Xiao⁷

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
² Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China.
³ Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
⁴ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Department of Cardiology, Laboratory of Experimental Cardiology, University Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; UMC Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
⁶ Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: [email protected].
⁷ Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China. Electronic address: [email protected].

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. 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.

Keywords: ADAR2; RNA editing; doxorubicin-induced cardiotoxicity; exercise; myocardial infarction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Cardiotoxicity / genetics
Cardiotoxicity / prevention & control
Doxorubicin / adverse effects
MicroRNAs* / genetics
Myocardial Infarction* / genetics
Myocytes, Cardiac
Rats

Substances

MicroRNAs
Doxorubicin