1. Academic Validation
  2. High-Mobility Group A1 Promotes Cardiac Fibrosis by Upregulating FOXO1 in Fibroblasts

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

  • Front Cell Dev Biol. 2021 Aug 26;9:666422. doi: 10.3389/fcell.2021.666422.
Qingwen Xie 1 2 3 Qi Yao 1 2 3 Tongtong Hu 1 2 3 Zhulan Cai 1 2 3 Jinhua Zhao 1 2 3 Yuan Yuan 1 2 3 Qing Qing Wu 1 2 3 Qi-Zhu Tang 1 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 2 Cardiovascular Research Institute, Wuhan University, Wuhan, China.
  • 3 Hubei Key Laboratory of Cardiology, Wuhan, China.
Abstract

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.

Keywords

FOXO1; cardiac dysfunction; cardiac fibrosis; fibroblasts; high-mobility group A1.

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