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.
Highlights
Cardiac fibrosis caused by various cardiac injuries is characterized by the production of excessive extracellular matrix (ECM) in the cardiac interstitium, leading to increased ventricular stiffness and diastolic dysfunction, and giving rise to heart failure (Gyongyosi et al, 2017)
We showed that High-mobility group A1 (HMGA1) promoted ISO- or angiotensin II (Ang II)-induced cardiac fibrosis and dysfunction in vivo
Myofibroblasts are widely considered to be the cause of cardiac fibrosis, and their excessive ECM secretion directly leads to the formation of scar tissue (Leask, 2015)
Summary
Cardiac fibrosis caused by various cardiac injuries is characterized by the production of excessive extracellular matrix (ECM) in the cardiac interstitium, leading to increased ventricular stiffness and diastolic dysfunction, and giving rise to heart failure (Gyongyosi et al, 2017). Isoproterenol (ISO), a β-adrenergic agonist, could increase cardiac fibroblasts (CF) proliferation, and collagen synthesis through excessive stimulation of β-adrenergic receptors in the heart (Benjamin et al, 1989). Other neurohumoral factors, such as angiotensin II (Ang II) and transforming growth factor β1 (TGF-β1), are increased during cardiac injury and act as key HMGA1 Promotes Cardiac Fibrosis contributors to cardiac fibrosis (Cucoranu et al, 2005; Flevaris et al, 2017). The mechanism that regulates the process of cardiac fibrosis is not fully understood
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