Abstract
Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial–mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.
Highlights
Fibrosis has recently been reported to be linked with a decreased extent of microvasculature and disrupted normal myocardial structures, as a result of excessive deposition of extracellular cell matrix mediated by recruitment of fibroblasts and endothelial dysfunction, but not much is known about its contribution to these conditions [1].Endothelial–mesenchymal transition (EndMT) is identified as a complex biological process during which endothelial cells lose various particular markers and obtain mesenchymal or myofibroblastic phenotype and express mesenchymal cell products [2]
Zeisberg et al [6] first revealed that cardiac fibrosis had notable association with the appearance of fibroblasts originating from endothelial cells, which suggested an analogous event to EndMT that occurs during formation of the atrioventricular cushion in the embryonic heart
We found that overexpression of c-Ski in Human coronary artery endothelial cells (HCAECs) blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without transforming growth factor-β (TGF-β) treatment
Summary
Fibrosis has recently been reported to be linked with a decreased extent of microvasculature and disrupted normal myocardial structures, as a result of excessive deposition of extracellular cell matrix mediated by recruitment of fibroblasts and endothelial dysfunction, but not much is known about its contribution to these conditions [1].Endothelial–mesenchymal transition (EndMT) is identified as a complex biological process during which endothelial cells lose various particular markers and obtain mesenchymal or myofibroblastic phenotype and express mesenchymal cell products [2]. EndMT process is closely associated with renal, lung, or cardiac fibrosis [4,5]. Zeisberg et al [6] first revealed that cardiac fibrosis had notable association with the appearance of fibroblasts originating from endothelial cells, which suggested an analogous event to EndMT that occurs during formation of the atrioventricular cushion in the embryonic heart. It has been reported that endothelin-1 derived c 2017 The Author(s).
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