DNA methylation regulates α‐smooth muscle actin expression during cardiac fibroblast differentiation

Abstract

Cardiac fibroblast (CF) differentiation to myofibroblasts expressing α-smooth muscle actin (α-SMA) plays a key role in cardiac fibrosis. Therefore, a study of the mechanism regulating α-SMA expression is a means to understanding the mechanism of fibroblast differentiation and cardiac fibrosis. Previous studies have shown that DNA methylation is associated with gene expression and is related to the development of tissue fibrosis. However, the mechanisms by which CF differentiation is regulated by DNA methylation remain unclear. Here, we explored the epigenetic regulation of α-SMA expression and its relevance in CF differentiation. In this study, we demonstrated that α-SMA was overexpressed and DNMT1 expression was downregulated in the infarct area after myocardial infarction. Treatment of CFs with transforming growth factor-β 1 (TGF-β 1 ) in vitro upregulated α-SMA expression via epigenetic modifications. TGF-β 1 also inhibited DNMT1 expression and activity during CF differentiation. In addition, α-SMA expression was regulated by DNMT1. Conversely, increasing DNMT1 expression levels rescued the TGF-β 1 -induced upregulation of α-SMA expression. Finally, TGF-β 1 regulated α-SMA expression by inhibiting the DNMT1-mediated DNA methylation of the α-SMA promoter. Taken together, our research showed that inhibition of the DNMT1-mediated DNA methylation of the α-SMA promoter plays an essential role in CF differentiation. In addition, DNMT1 may be a new target for the prevention and treatment of myocardial fibrosis.

Role of physical exercise in the regulation of epigenetic mechanisms in inflammation, cancer, neurodegenerative diseases, and aging process

“…In summary, epigenetic mechanisms are essential for gene expression regulation, influencing physiological processes such as differentiation (He et al, 2018), organogenesis (Boland, Nazor, & Loring, 2014;Schwanbeck, 2015), and aging (Ashapkin, Kutueva, & Vanyushin, 2017). On the other hand, the deregulation of epigenetic mechanisms is associated with several pathological processes, such as cancer (Fattahi, Kosari-monfared et al, 2018;Sharma, Kelly, & Jones, 2010) but also non-neoplastic disorders (e.g cardiovascular diseases, autoimmune diseases, diabetes, and some infectious diseases; Ogino et al, 2013).…”

Hydrogel mechanics regulate fibroblast DNA methylation and chromatin condensation

“…The data reported here also corroborate other findings in cellular phenotype with respect to substrate stiffness. 6,7,56,57 Compared to our collective understanding of phenotypic responses 3,15,16,28,58,59 and even MRTF-A 7,27,55,60 localization with respect to substrate mechanics and culture time, there are very few reports analyzing cell nuclear metrics, 37,38,[40][41][42] and even fewer for global DNA methylation, 61 in response to substrate mechanics over time. This is particularly interesting as SRF activity, which is mediated by nuclear MRTF-A, may be influenced by epigenetic modifications such as DNA methylation.…”

The protective effect of zinc, selenium, and chromium on myocardial fibrosis in the offspring of rats with gestational diabetes mellitus

“…43 α-Smooth muscle actin (α-SMA) is involved in smooth muscle contraction, which is considered as the marker for the differentiation of cardiac fibroblasts into myofibroblasts. 44 The connective tissue growth factor (CTGF) secreted by damaged cardiomyocytes participates in the cell proliferation, adhesion, and remodeling of the tissue structure. 45 Evidence has shown that the proteins associated with fibrosis, including Col-I, MMP-9, α-SMA, and CTGF, are up-regulated in the heart when exposed to hyperglycemia.…”