Cardiac fibrosis is associated with diverse heart diseases. In response to different pathological irritants, cardiac fibroblasts may be induced to proliferate and differentiate into cardiac myofibroblasts, thus contributing to cardiac fibrosis. TGF-β signaling is implicated in the development of heart failure through the induction of cardiac fibrosis. C-Ski, an inhibitory regulator of TGF-β signaling, has been reported to suppress TGF-β1-induced human cardiac fibroblasts' proliferation and ECM protein increase; however, the underlying molecular mechanism needs further investigation. In the present study, we demonstrated that c-Ski could ameliorate isoproterenol (ISO)-induced rat myocardial fibrosis model and TGF-β1-induced primary rat cardiac fibroblasts' proliferation, as well as extracellular matrix (ECM) deposition. The protein level of c-Ski was dramatically decreased in cardiac fibrosis and TGF-β1-stimulated primary rat cardiac fibroblasts. In recent decades, a family of small non-coding RNA, namely miRNAs, has been reported to regulate gene expression by interacting with diverse mRNAs and inducing either translational suppression or mRNA degradation. Herein, we selected miR-34a and miR-93 as candidate miRNAs that might target to regulate c-Ski expression. After confirming that miR-34a/miR-93 targeted c-Ski to inhibit its expression, we also revealed that miR-34a/miR-93 affected TGF-β1-induced fibroblasts' proliferation and ECM deposition through c-Ski. Taken together, we demonstrated a miR-34a/miR-93-c-Ski axis which modulates TGF-β1- and ISO-induced cardiac fibrosis in vitro and in vivo; targeting the inhibitory factors of c-Ski to rescue its expression may be a promising strategy for the treatment of cardiac fibrosis.

心脏纤维化与多种心脏病有关。响应于不同的病理刺激物，可诱导心脏成纤维细胞增殖并分化为心脏成肌纤维细胞，从而促进心脏纤维化。通过诱导心脏纤维化，TGF-β信号传导与心力衰竭的发展有关。据报道，C-Ski是TGF-β信号的抑制性调节剂，可抑制TGF-β1诱导的人心脏成纤维细胞的增殖和ECM蛋白的增加。然而，潜在的分子机制需要进一步研究。在本研究中，我们证明了c-Ski可以改善异丙肾上腺素（ISO）诱导的大鼠心肌纤维化模型和TGF-β1诱导的原代大鼠心脏成纤维细胞的增殖以及细胞外基质（ECM）沉积。在心脏纤维化和TGF-β1刺激的原代大鼠心脏成纤维细胞中，c-Ski的蛋白水平显着降低。在最近的几十年中，已经报道了一个小的非编码小RNA家族，即miRNA，通过与各种mRNA相互作用并诱导翻译抑制或mRNA降解来调节基因表达。在本文中，我们选择了miR-34a和miR-93作为可能靶向调控c-Ski表达的候选miRNA。在确认miR-34a / miR-93靶向c-Ski抑制其表达后，我们还揭示了miR-34a / miR-93通过c-Ski影响了TGF-β1诱导的成纤维细胞的增殖和ECM沉积。综上所述，我们证明了miR-34a / miR-93-c-Ski轴可调节TGF-β1和ISO诱导的心脏纤维化 已报道通过与多种mRNA相互作用并诱导翻译抑制或mRNA降解来调节基因表达。在本文中，我们选择了miR-34a和miR-93作为可能靶向调控c-Ski表达的候选miRNA。在确认miR-34a / miR-93靶向c-Ski抑制其表达后，我们还揭示了miR-34a / miR-93通过c-Ski影响TGF-β1诱导的成纤维细胞的增殖和ECM沉积。综上所述，我们证明了miR-34a / miR-93-c-Ski轴可调节TGF-β1和ISO诱导的心脏纤维化 已报道通过与多种mRNA相互作用并诱导翻译抑制或mRNA降解来调节基因表达。在本文中，我们选择了miR-34a和miR-93作为可能靶向调控c-Ski表达的候选miRNA。在确认miR-34a / miR-93靶向c-Ski抑制其表达后，我们还揭示了miR-34a / miR-93通过c-Ski影响TGF-β1诱导的成纤维细胞的增殖和ECM沉积。综上所述，我们证明了miR-34a / miR-93-c-Ski轴可调节TGF-β1和ISO诱导的心脏纤维化 在确认miR-34a / miR-93靶向c-Ski抑制其表达后，我们还揭示了miR-34a / miR-93通过c-Ski影响TGF-β1诱导的成纤维细胞的增殖和ECM沉积。综上所述，我们证明了miR-34a / miR-93-c-Ski轴可调节TGF-β1和ISO诱导的心脏纤维化 在确认miR-34a / miR-93靶向c-Ski抑制其表达后，我们还揭示了miR-34a / miR-93通过c-Ski影响TGF-β1诱导的成纤维细胞的增殖和ECM沉积。综上所述，我们证明了miR-34a / miR-93-c-Ski轴可调节TGF-β1和ISO诱导的心脏纤维化体外和体内; 靶向c-Ski的抑制因子以恢复其表达可能是治疗心脏纤维化的有前途的策略。