糖尿病心肌病中HuR调控成纤维细胞分泌导致心肌肥大EVs的机制研究

Diabetic cardiomyopathy (DCM) is associated with cardiac hypertrophy and fibrosis, leading to myocardial infarction. Cardiac fibroblasts (CFs) mediate fibrosis and release extracellular vesicles (EVs) that induce cardiomyocyte hypertrophy. However, the mechanism underlying the release of pathological EVs from CFs is not clear. It has been suggested that RNA binding protein facilitated the secretion of miRNA thorough EVs. Our previous study showed that HuR, a RNA binding protein, increased in diabetic heart in mouse model. Inhibition of HuR suppressed CFs induced cardiomyocyte hypertrophy in cell model. Therefore, the hypothesis of this project is “elevated HuR in DCM facilitates the secretion of miRNA via EVs that are released into intercellular space and induce cardiomyocyte hypertrophy ”. This project investigates: 1)The effects of EVs derived from CFs on cardiac hypertrophy during DCM; 2) The effects of inhibition or overexpression of HuR on the function of EVs derived from CFs during DCM; 3) The effects of HuR inhibitor, MS-444, on the treatment of DCM. This project will reveal a novel mechanism underlying the pathogenesis of DCM and provide new targets or concepts for the treatment of DCM.

糖尿病心肌病（DCM）伴随心肌肥大和纤维化，可导致心衰。心脏成纤维细胞（CFs）介导纤维化的发生，并可分泌细胞外囊泡（EVs）导致心肌细胞肥大，但EVs的分泌机理尚不清楚。有研究表明RNA结合蛋白可促进miRNA通过EVs的胞外转运。我们前期研究发现糖尿病小鼠心脏组织中RNA结合蛋白HuR表达明显上升，抑制CFs中的HuR可改善CFs介导的心肌肥大。因此，我们的研究假说是“DCM发病过程中，CFs中的HuR和病理性miRNA结合，促进携带的miRNA通过EVs分泌，导致心肌肥大”。本课题首先研究在DCM病理环境下CFs分泌的EVs对心肌肥大的影响；进一步探索DCM中HuR对CFs来源EVs内容物的调控机制；最后评价HuR抑制剂MS-444对DCM小鼠心肌肥大治疗作用。旨在揭示DCM伴随的心肌肥大的发病机制，为DCM的治疗提供新的靶点。

本课题主要研究糖尿病心肌病（DCM）发病过程中RNA结合HuR在介导成纤维细胞分泌导致心肌肥大的细胞外囊泡（EVs）中的作用。本课题首先利用DCM细胞和动物模型研究成纤维细胞来源EVs在心肌肥大发病中的作用，然后进一步研究此过程中HuR在调节成纤维细胞EVs功能中的作用，最后评价小分子HuR 抑制剂对小鼠DCM 伴随的心肌肥大的治疗作用。研究结果表明高糖高胰岛素刺激下成纤维细胞分泌的EVs可以导致乳鼠原代心肌细胞的肥大；进一步分析了HuR对成纤维分泌的EVs中miRNA成分的影响，发现过表达HuR可以导致成纤维细胞EVs中miRNA成分的变化，该EVs可以直接导致心肌细胞肥大，抑制HuR后DCM病理刺激后的成纤维细胞分泌的EVs不能造成心肌细胞肥大；最后评价了HuR抑制剂对小鼠DCM的治疗作用，发现HuR抑制剂DHTS可以改善长期高脂饮食造成的小鼠心肌肥大和心脏舒张功能障碍。以上结果表明了DCM发病过程中，HuR在介导成纤维细胞分泌导致心肌肥大EVs中的关键作用，并为开发DCM的治疗靶点和治疗策略提供了新的思路。