80%糖尿病患者最终都死于心血管疾病，其中糖尿病心肌病以其发病隐匿、机制不明、无有效治疗手段等特点严重危害患者健康，研究显示自噬在其中发挥重要作用。课题组前期研究发现，Mst1抑制心肌细胞自噬，恶化糖尿病小鼠心脏功能。本项目预实验发现，特异性敲除内皮细胞ERK5加重糖尿病小鼠心脏功能障碍，心肌细胞自噬水平下降，凋亡增加，外泌体分泌抑制剂显著改善上述指标，外泌体内含物分析发现敲除ERK5的内皮细胞来源的外泌体Mst1 mRNA含量显著增加。据此我们提出假说：特异性敲除ERK5的内皮细胞分泌富含功能性的Mst1 mRNA的外泌体至心肌细胞，促进心肌细胞Mst1蛋白的表达，进而抑制其自噬水平，促进凋亡。本课题组将从动物、细胞及分子水平，以内皮特异性敲除ERK5小鼠、心肌和内皮细胞模型为研究对象，运用超声、免疫荧光等技术，探讨ERK5在糖尿病心肌病发生发展中的作用和机制，为其防治提供新思路。

Eighty percent of diabetic patients died from cardiovascular diseases. Diabetic cardiomyopathy (DCM) is seriously endangering patients’ heath due to its hidden occultity, unclear mechanism and no effective treatment. Lots of study reported that autophagy plays a critical role in the development of DCM. Our previous study indicated that Mst1 deteriorated cardiac dysfunction in diabetic model by suppressing autophagy. The pre-experimental data shown that ERK5 specific deletion in endothelial cell aggravated cardiac dysfunction in diabetic mice and suppressed autophagy and promoted apoptosis in vitro. Exosome-secreted inhibitor reversed the detrimental effects mentioned above which indicated exosomes were involved in the regulation of cardiac function in ERK5-specific knockout mice. Analysis of the content of exosomes from endothelial cell shown more bioactive Mst1 mRNA after ERK5 knockdown. Accordingly, we established the hypothesis that ERK5 specific knockout in endothelial cells increased the content of exosomal Mst1 mRNA which could be incubated by cardiomyocytes and then promoted the expression of Mst1 in cardiomyocytes. The increased expression of Mst1 in myocardium inhibited autophagy and promoted apoptosis which impaired cardiac function in diabetic mice. We will use endothelial cell-specific ERK5 knockout mice, myocardial cells and endothelial cells as research objects and apply methods, such as ultrasound and immunofluorescence, to explore the function and role of ERK5 in the development of diabetic cardiomyopathy at the animal, cell, and molecular levels. The present project will enrich the mechanism and provide new therapeutic strategy of diabetic cardiomyopathy.