Relaxin alleviates TGFβ1-induced cardiac fibrosis via inhibition of Stat3-dependent autophagy
Relaxin alleviates TGFβ1-induced cardiac fibrosis via inhibition of Stat3-dependent autophagy
复制标题
松弛素通过抑制 Stat3 依赖性自噬减轻 TGF beta 1 诱导的心脏纤维化
DOI：
10.1016/j.bbrc.2017.09.110
复制
发表时间：
2017-12-02
影响因子：
3.1
通讯作者：
Li, Yue
中科院分区：
文献类型：
--
作者：
Yuan, Yue;Zhang, Yun;Li, Yue
心脏纤维化是心肌梗塞、心律失常、心肌病和心力衰竭等多种心脏病常见的病理特征。新出现的数据表明，自噬参与纤维化的合成。松弛素作为一种多效性激素，可减轻心肌纤维化和肥大，但其确切的分子机制尚不清楚。在这项工作中，我们评估松弛素的抗纤维化作用是否依赖于调节原代心脏成纤维细胞（CF）中的自噬。我们的研究结果表明松弛素显著减弱TGF β 1诱导的自噬，同时减少纤维化。此外，松弛素抑制Stat 3/Smad 3信号的磷酸化。我们观察到Stat 3基因的敲低可以同时抑制CFs中TGF β 1刺激的纤维化和自噬通量。更重要的是，我们同时给予松弛素和Stat 3敲低到CF中，与仅Stat 3敲低或松弛素处理相比，这不会引起自噬过程和胶原蛋白的进一步下调。这些数据表明松弛素依赖于Stat 3信号传导介导的自噬来改善TGF β诱导的纤维化。这项研究揭示了松弛素在心脏纤维化中先前未被认识到的抗纤维化作用，这是通过抑制Stat 3依赖性自噬来实现的，这意味着纤维化疾病的潜在治疗靶点。(C)2017由Elsevier Inc.出版
Cardiac fibrosis is a pathological feature common to a variety of heart diseases such as myocardial infarction, arrhythmias, cardiomyopathies and heart failure. Emerging data has indicted that autophagy is involved in fibrotic synthesis. Relaxin as a pleiotropic hormone can attenuate cardiac fibrosis and hypertrophy, however the exact molecular mechanism remains largely unknown. In this work, we evaluated whether the antifibrotic effect of relaxin relies on regulating autophagy in primary cardiac fibroblasts (CFs). Our results showed that relaxin significantly attenuated TGF beta 1-induced autophagy in parallel with the reduction of fibrosis. Moreover, relaxin inhibited the phosphorylation of Stat3/Smad3 signaling. Then we observed that knockdown of Stat3 synchronously suppressed the fibrogenesis and autophagic flux which was stimulated by TGF beta 1 in CFs. More importantly, we simultaneously administrated relaxin and Stat3 knockdown into CFs, which did not cause further downregulation of autophagy process and collagen protein compared with only Stat3 knockdown or relaxin treatment. These data suggested that relaxin ameliorates TGF beta-induced fibrosis dependent on Stat3 signaling-mediated autophagy. This study uncovered a previously unrecognized antifibrotic role of relaxin in cardiac fibrosis, which is achieved through the inhibition of Stat3-dependent autophagy, implying a potential therapeutic target in fibrotic diseases. (C) 2017 Published by Elsevier Inc.