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Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction

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′ untran...

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Detalles Bibliográficos
Autores principales: Yu, Peng, Song, Shuai, Zhang, Xiaokai, Cui, Shujun, Wei, Gang, Huang, Zihang, Zeng, Linqi, Ni, Ting, Sun, Aijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589712/
https://www.ncbi.nlm.nih.gov/pubmed/37816050
http://dx.doi.org/10.1073/pnas.2302482120
Descripción
Sumario: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.