Insl6对心肌纤维化的影响及机制研究

As a family member of the human relaxin peptides, Insulin like peptide 6 (Insl6) is closely related to human relaxin-2 and structurally homologous. Recent studies have demonstrated that Insl6 could ameliorate the inflammatory response of autoimmune myopathy and promote myofibroblast regeneration after muscle injury. However, the relationship between Insl6 and cardiac fibrosis-related cardiovascular disease has not been reported. Our pilot study revealed that Insl6 gene-knockout (KO) mice showed significantly more severe myocardial fibrosis phenotype when compared to wild-type mice, and human recombinant Insl6 could partially inhibit the Ang II-induced cardiac fibroblasts fibrosis. This project intends to establish a myocardial fibrosis model with Insl6-KO mice and Insl6-TG mice to verify the anti-fibrotic effect of Insl6 in vivo study; and in vitro, to explore the relationship between anti-fibrotic effect of Insl6 and Notch/TGF-β/Smad signaling pathway and its related mechanisms, which would certainly provide new evidence for the therapeutic target of myocardial fibrosis-related cardiovascular disease.

摘要：.Insl6属于人类松弛素肽家族成员，在进化上与人松弛素2有密切关系，在结构上具有同源性。近期研究发现具有改善自身免疫性肌病炎症反应、促进肌肉损伤后肌成纤维细胞再生的作用，但Insl6与心肌纤维化相关性心血管疾病尚无研究报道。我们前期实验发现与野生型小鼠相比，Insl6基因缺失小鼠显示出更严重的心肌纤维化的表型，人重组Insl6蛋白能部分抑制AngII诱导的心肌成纤维细胞纤维化表现。本项目拟采用Insl6-KO、Insl6-TG小鼠建立心肌纤维化模型，在整体模型上探索Insl6是否具有抗心肌纤维化作用；再通过体外细胞模型，探索Insl6抗纤维化作用与Notch/TGF-β/Smad信号通路的关系，明确相关机制，为心肌纤维化相关性心血管疾病的治疗靶点提供新的证据。

纤维化是多种因素参与的器官损伤修复的病理过程，是多种器官衰竭的必经之路。目前临床缺乏治疗纤维化的有效手段。本研究主要探讨胰岛素样因子6（Insl6）对心脏纤维化及肾脏纤维化的作用。发现无论在心脏或是肾脏，Insl6均具有抗纤维化作用。并通过体外模型，证实其抗纤维化作用机制，可能与TGF-Smads通路有关。