冠脉功能受外泌体调节。Urocortin（UCN）能保护糖尿病心血管功能，然而外泌体是否参与其中还未见报道。申请者前期研究发现UCN能抑制巨噬细胞外泌体诱导的冠脉内皮细胞凋亡，提示巨噬细胞外泌体是UCN保护冠脉内皮的新靶点。糖尿病病人体内蓄积大量甲基乙二醛（MGO），申请者发现MGO诱导巨噬细胞产生的外泌体明显损伤冠脉内皮的舒张功能，提示该过程或许是UCN抗糖尿病冠脉病变的关键机制。miRNA随外泌体在细胞间传递，调节糖尿病血管功能。有趣的是，UCN不仅调控多种miRNA的表达，还可抑制MGO产生氧化应激、生成下游产物，因此，我们推测UCN对抗MGO对巨噬细胞外泌体的影响，并保护糖尿病冠脉内皮功能，其机制是调控外泌体中的miRNA。本项目拟在小鼠糖尿病模型中，研究巨噬细胞外泌体对冠脉内皮功能的损伤作用，探索UCN在其中的调控作用机制。这将为探索UCN作为糖尿病冠脉病变的防治靶标提供依据。

The function of the coronary artery is regulated by the exosomes. Urocortin (UCN) can protect the cardiovascular function of diabetes. However, it has not been reported whether the exosomes are involved in it. Our previous studies showed that UCN could significantly inhibit macrophage-derived exosomes-induced coronary endothelial cell apoptosis, suggesting that the macrophage-derived exosomes is a new target for UCN to protect coronary artery endothelial cells. Methylglyoxal (MGO) accumulates extensively in diabetic patients. We found that MGO-stimulated macrophage-derived exosomes impaired the endothelium-dependent vasodilation of coronary artery, suggesting that this process may be the key mechanism of UCN in the treatment of diabetic coronary artery disease. Interestingly, UCN not only regulate the expression of various miRNAs, but also inhibit MGO-induced oxidative stress and the production of MGO downstream products. Therefore, we hypothesized that UCN would inhibit the effect of MGO on the exosomes of macrophage and protect the endothelial function of the coronary arteries via regulating miRNA in exosomes. This project proposes to develop a diabetic mouse model and investigate the harmful effects of macrophage-derived exosomes on the endothelial function of the coronary arteries in mice and explore the underlying regulatory mechanism of UCN. This study is to provide new insights into the role of UCN in diabetic coronary artery disease and hence as a therapeutic target for diabetes.