NOD1/RIP2介导的线粒体稳态在太子参环肽B抗糖尿病心肌病中的作用机制研究

我国是世界上糖尿病人数最多的国家。作为糖尿病心血管疾病的并发症，糖尿病心肌病（DCM）是主要的危险因素，然而其发病机制不清，尚无针对性治疗药物。根据中医糖尿病益气疗法，申请者前期筛选出了益气药太子参中的活性成分太子参环肽B，并且通过DCM小鼠模型研究发现其改善心肌功能抗心肌细胞凋亡效果显著。同时，体外高糖诱导心肌细胞损伤模型研究发现它能显著改善线粒体功能，维护线粒体形态，抗心肌细胞凋亡。分子生物学实验进一步证实，NOD1/RIP2通路是DCM的潜在治疗靶点，也是太子参环肽B的干预靶点。基于以上前期结果，本项目拟通过动物、细胞、分子生物学等多层次实验手段验证：太子参环肽B通过抑制NOD1/RIP2通路激活Sirt3，促进OPA1去乙酰化，维持线粒体稳态，抑制心肌细胞凋亡，改善DCM的科学假说。本研究不仅揭示了DCM新的治疗靶点，而且为太子参环肽B作为DCM的临床治疗药物提供了实验依据。

China is the country with the largest number of diabetic patients in the world. Diabetic cardiomyopathy (DCM) is a serious cardiac complication caused by diabetes, which brings a heavy burden not only to the patients but also to the country. We found an extract-Pseudostellaria Heterophyllin B, from traditional Chinese medicine, which can effectively alleviate the symptoms of cardiomyopathy in diabetic mice, improve their cardiac function and ameliorate the cardiac pathological change. At the same time, it can improve mitochondrial function, increase mitochondrial length, and thus inhibit apoptosis in the high-glucose cultured cardiomyocytes. It is also showed that Heterophyllin B could inhibit the over-activated NOD1/RIP2 pathway and activate Sirt3 / OPA1 signal in DCM cardiomyocytes. Based on the previous results, this project intends to verify the scientific hypothesis through animal, cell, molecular and other experiments, that is, Heterophyllin B can activate Sirt3 by inhibiting NOD1/RIP2 pathway, promoting deacetylation of OPA1, maintain mitochondrial homeostasis, inhibit cardiomyocyte apoptosis and eventually alleviate DCM. This study will not only reveal the pathogenesis of DCM, but also provide new targets and novel therapeutic solution for DCM. In conclusion, this project shows great importance for DCM treatment.