心肌细胞-成纤维细胞对话机制在糖尿病心肌纤维化中的作用及绞股蓝皂苷的干预研究

心肌细胞（CM）和心脏成纤维细胞（CF）的相互作用在糖尿病心脏并发症中发挥重要作用，但二者的“对话”形式及机制仍不明确。我们前期研究发现传统中药有效成分绞股蓝总皂苷（Gp）可通过抑制NLRP3炎症小体活化改善高糖诱导的心肌细胞损伤。炎症小体活化是否作为CM-CF的“对话”媒介介导糖尿病心肌纤维化，以及Gp是否基于此发挥心肌保护作用？目前尚不清楚。本项目拟：①在大鼠及NLRP3基因敲除小鼠糖尿病模型（I型及II型）中检测炎症小体活化、心脏纤维化程度及Gp的心脏保护效果；②利用CM-CF体外共培养体系，深入探讨高糖环境下CM损伤对CF炎症小体活化和向肌成纤维细胞转化的影响，并检测Gp在此过程中的作用；③探究Gp是否通过抑制CF炎症小体活化，进而降低CF中胶原蛋白合成和改善CM损伤。项目的开展将为糖尿病组织、器官并发症的机制研究开辟新途径，同时为新药研发提供新靶点。

The interaction between cardiomyocyte (CM) and cardiac fibroblast (CF) plays an important role in diabetic cardiac complications, while the form and mechanisms of “cross-talk” between CM and CF are still undoubtedly indispensable. Our previous study found that the traditional Chinese medicine gypenosides (Gp) could improve myocardial damage through inhibiting NLRP3 inflammasome activation which was induced by high glucose. Whether inflammasome could act as a mediator between CM and CF and participate in the diabetic myocardial fibrosis, and whether Gp protected myocardium from damage remain unclear. In the present study, First, we will establish diabetic animal model with wild rats and NLRP3 KO mouse, then detect inflammasome activation, myocardial fibrosis and the role of Gp in the model. Second, we will further investigate the effect of high glucose-induced myocyte damage on fibroblast inflammasome activation and the differentiation from CF to myofibroblast. At last, we need to address is whether Gp could decrease the collagen levels in CF and improve CM damage through inhibiting inflammasome activation in CF. In conclusion, our study will open up a new way for the mechanism investigation about diabetic cardiac complications, and provide a new target for medicine development.