基于miR-21/TGF-β/snail介导的内皮间质转化研究糖尿病心肌病“主客交”病理机制及三甲散干预作用

Diabetic cardiomyopathy (DCM) is the leading cause of heart failure and death in diabetic patients. Its pathogenesis is complex, however, myocardial fibrosis is the characteristic pathological change. In view of that the central link of myocardial fibrosis is the activation and proliferation of cardiac fibroblasts and excessive accumulation of extracellular matrix, inhibiting proliferation activation of fibroblasts is the key to prevent myocardial fibrosis. The new researches have showed that endothelial mesenchymal transition (EnMT) is an important mechanism on activation and proliferation of cardiac fibroblasts, and miR-21/TGF-β/snail may mediate this process. Moreover, the preliminary studies have showed that "Deficiency, toxin and stasis" is the pathological factors of diabetes and its chronic complications, then long into the heart meridian, damage the heart, and initiate DCM eventually. So it conforms to the "zhu-ke jiao" pathogenesis essence of Chinese medicine. Therefore this research take EnMT mediated by miR-21/TGF-β/snail as the breakthrough point, aim to prove the "zhu-ke jiao" pathogenesis of DCM with intervention effects of San-jia powder, thus to investigate the molecular mechanism of myocardial fibrosis in DCM and the action mechanism of San-jia powder. This will provide new ideas for preventing and curing DCM.

糖尿病心肌病（DCM）是引起糖尿病患者心衰和死亡的主要原因。DCM发病机制复杂，而心肌纤维化是其特征性病理改变。心肌纤维化的中心环节是心肌成纤维细胞的增殖活化及细胞外基质过度堆积。因此抑制成纤维细胞的增殖活化是阻止心肌纤维化的关键。最新研究表明，内皮间质转化是心肌成纤维细胞增殖活化的重要机制，有线索显示miR-21/TGF-β/snail介导了这一过程。课题的前期研究表明，“虚、毒、瘀”是糖尿病及其慢性并发症的病机要素，病久迁延则痰湿瘀毒留滞心络，损伤心脏，发生DCM，符合“主客交”病机实质。本课题以miR-21/TGF-β/snail 介导的内皮间质转化为切入点，用三甲散的干预作用对DCM“主客交”病机进行反证，并深入探讨DCM心肌纤维化的分子机制和三甲散的作用机制，为防治DCM提供新思路。

糖尿病心肌病（DCM）是由糖尿病引起的特发性心肌病变，心肌纤维化是其特征性病理改变，但具体病理机制尚未完全明确，亦无特效治疗药物。本课题以miR-21/TGF-β/snail介导的内皮间质转化作为切入点，用中医方药三甲散对大鼠模型和细胞模型进行干预，从体内体外两个层面探讨DCM心肌纤维化的分子机制和三甲散的干预作用。研究结果显示，DCM模型鼠的心肌组织呈典型纤维化改变，纤维化标志物collagenⅠ和collagenⅢ表达增强，血清LN、HA水平升高，心功能受损；高糖诱导的心脏微血管内皮细胞（CMECs）向成纤维细胞转化。在DCM模型鼠和高糖诱导的CMECs中均发现内皮细胞标志物降低而间质细胞标志物升高，同时miR-21、TGF-β1、snail-1、snail-2表达上调，Smad7、PTEN表达下调，表明内皮间质转化是糖尿病心肌纤维化的重要病理机制，其过程受miR-21/TGF-β/snail信号通路分子调控。而使用三甲散能降低FBG，改善心功能，减少纤维化，逆转内皮间质转化，其作用机理与调控miR-21/TGF-β/snail信号通路有关。本课题初步阐明了DCM的病理机制，验证了三甲散的作用效果，初步揭示了该方的作用机理，为该方的临床应用提供了实验依据，并丰富了DCM的“主客交”中医病机内涵，为中医药防治糖尿病心肌病提供了新思路。

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