Abstract
Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between −516 and −224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.
Highlights
Cardiac fibrosis is generally considered an adaptive response to adversarial stimuli when the heart is exposed to various injuries
In order to compare chloride channel accessory 2 (Clca2) expression in quiescent cardiac fibroblasts and activated cardiac fibroblasts, C57B/6 mice were subjected to the left-anterior descending (LAD) procedure to induce myocardial infarction; previous investigations have shown that fibroblast-myofibroblast transition (FMyT) peaks at 7 day after the surgery (Kanisicak et al, 2016)
It was observed that compared to the shamoperated mice, expression levels of Acta2 and Col1a1, two typical myofibroblast markers, were significantly up-regulated in the primary cardiac fibroblasts isolated from the LAD-operated mice; on the contrary, Clca2 expression was down-regulated in the activated cardiac fibroblasts compared to the quiescent cardiac fibroblasts (Figure 1A)
Summary
Cardiac fibrosis is generally considered an adaptive response to adversarial stimuli when the heart is exposed to various injuries. Myofibroblasts produce multiple extracellular matrix proteins (e.g., type I collagen, type III collagen, fibronectin) to promote ventricular remodeling and maintain myocardial integrity (van den Borne et al, 2010). After the recession of injurious stimuli, myofibroblasts are no longer needed and must be removed or resolved to terminate cardiac fibrogenesis. Persistent presence of myofibroblasts in the heart or failure of resolution often leads to aberrant and averse cardiac remodeling and increased rigidity of the myocardium dampening heart function. Cardiac fibrosis is frequently observed and associated with poor diagnosis in patients with heart failure (Gonzalez et al, 2018)
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