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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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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
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author Yu, Peng
Song, Shuai
Zhang, Xiaokai
Cui, Shujun
Wei, Gang
Huang, Zihang
Zeng, Linqi
Ni, Ting
Sun, Aijun
author_facet Yu, Peng
Song, Shuai
Zhang, Xiaokai
Cui, Shujun
Wei, Gang
Huang, Zihang
Zeng, Linqi
Ni, Ting
Sun, Aijun
author_sort Yu, Peng
collection PubMed
description 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.
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spelling pubmed-105897122023-10-22 Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction Yu, Peng Song, Shuai Zhang, Xiaokai Cui, Shujun Wei, Gang Huang, Zihang Zeng, Linqi Ni, Ting Sun, Aijun Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-10-10 2023-10-17 /pmc/articles/PMC10589712/ /pubmed/37816050 http://dx.doi.org/10.1073/pnas.2302482120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Yu, Peng
Song, Shuai
Zhang, Xiaokai
Cui, Shujun
Wei, Gang
Huang, Zihang
Zeng, Linqi
Ni, Ting
Sun, Aijun
Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title_full Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title_fullStr Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title_full_unstemmed Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title_short Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction
title_sort downregulation of apoptotic repressor aven exacerbates cardiac injury after myocardial infarction
topic Biological Sciences
url 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
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