GRIM-19介导的SIRT1/STAT3通路在糖尿病心肌纤维化中的作用和机制研究

Diabetic myocardial injury is one of the important complications of diabetes, and myocardial fibrosis is important pathological changes in the diabetic cardiomyopathy, but the mechanism is still not clear. Recently, we found that the expression of GRIM-19 which can be induced by retinoic acid/interferon is very abundant in the myocardium, and the expression of GRIM-19 is reduced when the diabetic myocardium damaged. While, the overexpression of GRIM-19 in mice can reduce the fibrosis induced by the diabetic myocardial injury. Further studies have shown that the changes of GRIM-19 can affect the expression of SIRT1, which can participate in the regulation of the STAT3 pathway. Therefore, we hypothesized that the signaling pathway of GRIM-19-SIRT1-STAT3 plays a major role in the regulation of the diabetic myocardial fibrosis. In this research, the role of GRIM-19 on the changes of STAT3 pathway and myocardial fibrosis in diabetes mellitus were studied. And the primary myocardial fibroblasts (GRIM-19 knock over or overexpression), GRIM-19 overexpressed mice were used, and specifically intervened with SIRT1/STAT3 molecules in vivo and vitro. And then we try to figure out the role and molecular mechanism of GRIM-19 in the diabetic myocardial fibrosis, in order to provide possible theoretical basis and potential therapeutic targets for effective intervention of diabetic myocardial injury.

糖尿病心肌损伤是糖尿病的重要并发症，而心肌纤维化是其重要病理改变，其机制尚待阐明。我们近期研究发现，维甲酸/干扰素诱导的细胞凋亡相关基因GRIM-19在心肌表达十分丰富，但在糖尿病心肌损伤时表达明显降低，而GRIM-19过表达可以显著减轻糖尿病模型小鼠心肌纤维化；进一步研究发现干预GRIM-19能影响SIRT1的表达，而 SIRT1参与调控STAT3通路。据此我们推测，GRIM-19-SIRT1-STAT3信号通路在糖尿病心肌纤维化中发挥重要调控作用。本项目拟利用GRIM-19敲低和过表达的原代心肌成纤维细胞和GRIM-19转基因小鼠，并干预SIRT1/STAT3分子，从细胞和在体水平研究高血糖条件下 GRIM-19对心肌成纤维细胞的影响及其与SIRT1-STAT3通路的调控关系，阐明GRIM-19在糖尿病心肌纤维化中的作用和分子机制，为有效干预糖尿病心肌损伤提供可能的理论依据及潜在靶点。

纤维化是糖尿病导致的心脏及血管重要病理改变之一，研究其发生机制对糖尿病心肌病以及动脉粥样硬化的治疗有重要意义。GRIM-19作为维甲酸/干扰素诱导的细胞凋亡相关基因，其在心肌及平滑肌细胞中的功能值得研究。本研究从分子、细胞水平，利用GRIM-19敲低的原代心肌成纤维细胞以及原代血管平滑肌细胞，研究在糖尿病条件下STAT3通路和心肌纤维化以及血管平滑肌细胞的增殖及迁移变化，阐明GRIM-19参与调控SIRT1/STAT3通路和糖尿病心肌纤维化机制，以及在血管重构中的作用；我们研究发现GRIM-19在心肌及平滑肌细胞内表达十分丰富，其在糖尿病心肌及平滑肌细胞损伤时表达降低，进一步研究表明GRIM-19改变能影响SIRT1的表达，同时SIRT1参与调控STAT3通路。我们的研究结果提示GRIM-19-SIRT1-STAT3信号通路在糖尿病心肌纤维化中起重要作用，同时GRIM-19也参与血管平滑肌细胞增殖及迁移。研究可为糖尿病心肌及血管重构提供潜在靶点。