Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 42; pp. 1 - e2302482120
• Main Authors: Yu, Peng, Song, Shuai, Zhang, Xiaokai, Cui, Shujun, Wei, Gang, Huang, Zihang, Zeng, Linqi, Ni, Ting, Sun, Aijun
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 17.10.2023
• Subjects: 3' Untranslated regions; Apoptosis; Binding sites; Biological Sciences; Cardiomyocytes; Congestive heart failure; Down-regulation; Gene expression; Heart attacks; Morbidity; Myocardial infarction; Poly(A)-binding protein; Polyadenylation; Therapeutic targets
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2302482120

Myocardial infarction (MI) is a leading cause of heart failure (HF), associated with morbidity and mortality worldwide. As an essential part of gene expression regulation, the role of alternative polyadenylation (APA) in post-MI HF remains elusive. Here, we revealed a global, APA-mediated, 3′ untranslated region (3′ UTR)-lengthening pattern in both human and murine post-MI HF samples. Furthermore, the 3′ UTR of apoptotic repressor gene, AVEN , is lengthened after MI, contributing to its downregulation. AVEN knockdown increased cardiomyocyte apoptosis, whereas restoration of AVEN expression substantially improved cardiac function. Mechanistically, AVEN 3′ UTR lengthening provides additional binding sites for miR-30b-5p and miR-30c-5p, thus reducing AVEN expression. Additionally, PABPN1 (poly(A)-binding protein 1) was identified as a potential regulator of AVEN 3′ UTR lengthening after MI. Altogether, our findings revealed APA as a unique mechanism regulating cardiac injury in response to MI and also indicated that the APA-regulated gene, AVEN , holds great potential as a critical therapeutic target for treating post-MI HF.