Downregulation of apoptotic repressor <i>AVEN</i> exacerbates cardiac injury after myocardial infarction.

Abstract

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, <i>AVEN</i>, is lengthened after MI, contributing to its downregulation. <i>AVEN</i> knockdown increased cardiomyocyte apoptosis, whereas restoration of <i>AVEN</i> expression substantially improved cardiac function. Mechanistically, <i>AVEN</i> 3' UTR lengthening provides additional binding sites for miR-30b-5p and miR-30c-5p, thus reducing AVEN expression. Additionally, <i>PABPN1</i> (poly(A)-binding protein 1) was identified as a potential regulator of <i>AVEN</i> 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, <i>AVEN</i>, holds great potential as a critical therapeutic target for treating post-MI HF.