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(HCAEC)有可能经历纤维化内皮-间充质转变(EndMT),这会导致产生基质的成纤维细胞,从而促进心脏纤维化的发病机理。最近,已证明原纤维化细胞因子转化生长因子-β(TGF-β)是关键的致病性驱动因子,已被证实可诱导EndMT。 C-Ski是TGF-β信号传导的重要调节剂。然而,在很大程度上没有阐明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。在本研究中,我们用不同浓度的TGF-β处理HCAEC,以诱导EndMT。我们发现,无论是否使用TGF-β处理,HCAEC中c-Ski的过表达要么通过阻碍波形蛋白,蜗牛,Slug和Twist的表达而阻断EndMT,同时增强CD31的表达。相反,抑制c-Ski进一步增强了EndMT。当前,miRNA表达障碍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,这已通过荧光素酶测定法进行了验证。 C-Ski表达受到miR-155的负调控。 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的作用可以被miR-155部分恢复。总而言之,这些发现将阐明miR-155通过c-Ski调节TGF-β诱导的HCAECs EndMT通过影响心脏纤维化的作用和机制,而miR-155 / c-Ski可能代表了新型的生物标志物和治疗靶点。心脏纤维化的治疗。

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