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.

译文

人冠状动脉内皮细胞 (HCAECs) 具有发生纤维化的内皮-间质转化 (EndMT) 的潜力,这导致产生基质的成纤维细胞,从而有助于心脏纤维化的发病机理。最近,纤维化细胞因子转化生长因子-β (TGF-β) 被证明是关键的致病驱动因素,已被证实可诱导EndMT。C-ski是TGF-β 信号的重要调节因子。然而,c-Ski的详细作用以及c-Ski影响HCAECs中TGF-β 诱导的EndMT的分子机制尚未得到很大的阐明。在本研究中,我们用不同浓度的TGF-β 处理HCAECs以诱导EndMT。我们发现,有或没有TGF-β 处理,HCAECs中c-Ski的过表达通过阻碍波形蛋白,蜗牛,Slug和Twist的表达来阻断EndMT,同时增强CD31的表达。相比之下,抑制c-ski进一步增强了EndMT。目前,miRNA表达紊乱经常被报道与心脏纤维化有关。通过使用在线工具,我们将miR-155视为可以靶向c-Ski的候选miRNA,使用荧光素酶分析验证了这一点。C-Ski表达受miR-155负调节。TGF-β 诱导的EndMT被miR-155沉默抑制; TGF-β 对波形蛋白,CD31,蜗牛,Slug和Twist的作用可以通过miR-155部分恢复。总之,这些发现将阐明miR-155通过c-Ski调节TGF-β 诱导的HCAECs EndMT以影响心脏纤维化的作用和机制,并且miR-155/c-Ski可能代表治疗心脏纤维化的新型生物标志物和治疗靶标。

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