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High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts

High-mobility group A1 (HMGA1) acts as a transcription factor in several cardiovascular diseases. However, the implications of HMGA1 in cardiac fibrosis remain unknown. Here, we investigated the impact of HMGA1 on cardiac fibrosis. A mouse cardiac fibrosis model was constructed via subcutaneous inje...

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Autores principales: Xie, Qingwen, Yao, Qi, Hu, Tongtong, Cai, Zhulan, Zhao, Jinhua, Yuan, Yuan, Wu, Qing Qing, Tang, Qi-zhu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427498/
https://www.ncbi.nlm.nih.gov/pubmed/34513822
http://dx.doi.org/10.3389/fcell.2021.666422
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author Xie, Qingwen
Yao, Qi
Hu, Tongtong
Cai, Zhulan
Zhao, Jinhua
Yuan, Yuan
Wu, Qing Qing
Tang, Qi-zhu
author_facet Xie, Qingwen
Yao, Qi
Hu, Tongtong
Cai, Zhulan
Zhao, Jinhua
Yuan, Yuan
Wu, Qing Qing
Tang, Qi-zhu
author_sort Xie, Qingwen
collection PubMed
description High-mobility group A1 (HMGA1) acts as a transcription factor in several cardiovascular diseases. However, the implications of HMGA1 in cardiac fibrosis remain unknown. Here, we investigated the impact of HMGA1 on cardiac fibrosis. A mouse cardiac fibrosis model was constructed via subcutaneous injection of isoproterenol (ISO) or angiotensin II (Ang II) infusion. Adult mouse cardiac fibroblasts (CFs) were isolated and cultured. CFs were stimulated with transforming growth factor-β1 (TGF-β1) for 24 h. As a result, HMGA1 was upregulated in fibrotic hearts, as well as TGF-β-stimulated CFs. Overexpression of HMGA1 in CFs aggravated TGF-β1-induced cell activation, proliferation, and collagen synthesis. Overexpression of HMGA1 in fibroblasts, by an adeno-associated virus 9 dilution system with a periostin promoter, accelerated cardiac fibrosis and cardiac dysfunction. Moreover, HMGA1 knockdown in CFs inhibited TGF-β1-induced cell activation, proliferation, and collagen synthesis. Mechanistically, we found that HMGA1 increased the transcription of FOXO1. The FOXO1 inhibitor AS1842856 counteracted the adverse effects of HMGA1 overexpression in vitro. HMGA1 silencing in mouse hearts alleviated Ang II-induced cardiac fibrosis and dysfunction. However, FOXO1 knockdown in mouse hearts abolished the deteriorating effects of HMGA1 overexpression in mice. Collectively, our data demonstrated that HMGA1 plays a critical role in the development of cardiac fibrosis by regulating FOXO1 transcription.
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spelling pubmed-84274982021-09-10 High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts Xie, Qingwen Yao, Qi Hu, Tongtong Cai, Zhulan Zhao, Jinhua Yuan, Yuan Wu, Qing Qing Tang, Qi-zhu Front Cell Dev Biol Cell and Developmental Biology High-mobility group A1 (HMGA1) acts as a transcription factor in several cardiovascular diseases. However, the implications of HMGA1 in cardiac fibrosis remain unknown. Here, we investigated the impact of HMGA1 on cardiac fibrosis. A mouse cardiac fibrosis model was constructed via subcutaneous injection of isoproterenol (ISO) or angiotensin II (Ang II) infusion. Adult mouse cardiac fibroblasts (CFs) were isolated and cultured. CFs were stimulated with transforming growth factor-β1 (TGF-β1) for 24 h. As a result, HMGA1 was upregulated in fibrotic hearts, as well as TGF-β-stimulated CFs. Overexpression of HMGA1 in CFs aggravated TGF-β1-induced cell activation, proliferation, and collagen synthesis. Overexpression of HMGA1 in fibroblasts, by an adeno-associated virus 9 dilution system with a periostin promoter, accelerated cardiac fibrosis and cardiac dysfunction. Moreover, HMGA1 knockdown in CFs inhibited TGF-β1-induced cell activation, proliferation, and collagen synthesis. Mechanistically, we found that HMGA1 increased the transcription of FOXO1. The FOXO1 inhibitor AS1842856 counteracted the adverse effects of HMGA1 overexpression in vitro. HMGA1 silencing in mouse hearts alleviated Ang II-induced cardiac fibrosis and dysfunction. However, FOXO1 knockdown in mouse hearts abolished the deteriorating effects of HMGA1 overexpression in mice. Collectively, our data demonstrated that HMGA1 plays a critical role in the development of cardiac fibrosis by regulating FOXO1 transcription. Frontiers Media S.A. 2021-08-26 /pmc/articles/PMC8427498/ /pubmed/34513822 http://dx.doi.org/10.3389/fcell.2021.666422 Text en Copyright © 2021 Xie, Yao, Hu, Cai, Zhao, Yuan, Wu and Tang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Xie, Qingwen
Yao, Qi
Hu, Tongtong
Cai, Zhulan
Zhao, Jinhua
Yuan, Yuan
Wu, Qing Qing
Tang, Qi-zhu
High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title_full High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title_fullStr High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title_full_unstemmed High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title_short High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts
title_sort high-mobility group a1 promotes cardiac fibrosis by upregulating foxo1 in fibroblasts
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427498/
https://www.ncbi.nlm.nih.gov/pubmed/34513822
http://dx.doi.org/10.3389/fcell.2021.666422
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