GLP-1（9-36）酰胺对糖尿病心肌病的保护作用及其分子机制的研究

糖尿病心肌病是导致糖尿病患者心力衰竭及死亡的主要原因，目前仍缺乏有效治疗手段。心肌细胞氧化应激、过度自噬和凋亡在糖尿病心肌病的发生发展中有着重要作用，是近年研究热点。GLP-1（9-36）酰胺是胰高血糖素样肽-1(GLP-1)降解产物，失去促胰岛素分泌能力，其生物学功能尚未得到充分认识。我们前期研究发现GLP-1（9-36）显著缓解高糖诱导原代心肌细胞氧化应激、过度自噬及凋亡，用CD36抑制剂可阻断GLP-1（9-36）对高糖诱导心肌细胞氧化应激的保护作用。因此我们假设：GLP-1（9-36）可能通过抑制高糖诱导心肌细胞氧化应激、过度自噬和凋亡，发挥对糖尿病心肌病的保护作用。本项目将利用心肌特异性CD36敲除小鼠、原代心肌细胞，从动物和细胞两个层面完善对GLP-1生物学功能的认识，尤其是证明GLP-1（9-36）酰胺对糖尿病心肌病的保护作用，为糖尿病心肌病的防治提供新的思路和靶点。

Diabetic cardiomyopathy (DCM) is the major cause of heart failure and death in diabetic patients, and there are no effective treatments other than heart transplantation. Oxidative stress, excessive autophagy and apoptosis play essential roles in the progression of DCM. GLP-1 (7–36) amide, as an attractive therapeutic agent for diabetes, is rapidly metabolized to a truncated GLP-1 (9–36) amide. The biological function of GLP-1 (9–36) amide has not been fully understood. Our pilot studies showed that GLP-1(9–36) amide significantly suppressed oxidative stress, excessive autophagy and apoptosis induced by high glucose in primary cardiomyocytes. We also found that specific CD36 inhibitor could block the antioxidant cardioprotective effect of GLP-1 (9–36) amide. We therefore hypothesize that GLP-1 (9–36) amide protects against DCM via improving oxidative stress, excessive autophagy and apoptosis in cardiomyocytes. To prove this hypothesis, this project will utilize CD36 cardiomyocyte-specic deficency mice, and primary cardiomyocytes to investigate the protective role of GLP-1 (9–36) amide in DCM, and its mechanisms.