索马鲁肽对早期2型糖尿病心肌病大鼠mTOR信号通路的干预作用

Intervention of Semaglutide on the Expression of mTOR Signaling Pathway in the Early Stage of Diabetic Cardiomyopathy Rats

关键词:  糖尿病心肌病  索马鲁肽  自噬损伤  mTOR信号通路

Key words:  diabetic cardiomyopathy  semaglutide  autophagy  mTOR signaling pathway

摘要:

目的 探讨索马鲁肽对糖尿病心肌病大鼠心肌组织哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路表达的干预作用。方法 高脂饮食5周后，腹腔注射链脲佐菌素建立2型糖尿病大鼠模型，实验将大鼠分为正常对照组、糖尿病2周、4周模型组和索马鲁肽组，索马鲁肽组在造模成功后给予索马鲁肽灌胃处理。4周后，各组动物进行血清学检测，包括空腹血糖、总胆固醇、甘油三酯、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-C）、空腹胰岛素，超声心动图检测心功能相关指标，Western blot检测心肌mTOR、p-mTOR、S6K1、Atg5和P62蛋白表达变化。结果 与正常对照组比较，2型糖尿病大鼠2周和4周模型血清中总胆固醇、甘油三酯、LDL-C水平显著升高，HDL-C水平显著降低；索马鲁肽组空腹血糖值趋于正常，HDL-C水平升高显著（P<0.05），LDL-C水平显著降低（P<0.01）。相对于正常对照组，糖尿病模型组大鼠心肌组织中mTOR、p-mTOR、S6K1的表达与正常对照组相比随时间持续增加（P<0.01），自噬相关蛋白Atg5和P62表达也显著增加（P<0.05），而索马鲁肽组均显示出降低趋势。结论 在早期糖尿病心肌病的发生发展过程中，索马鲁肽对mTOR信号通路具有抑制作用，能降低心肌细胞自噬损伤的发生。

Abstract:

OBJECTIVE To investigate the changes of mTOR signaling pathways under the intervention of semaglutide. METHODS The type 2 diabetes rat model was established by an injection ofstreptozocin after five-week of high fat diet. The rats were divided into control group, 2 weeks model group, 4 weeks model group, and semaglutide group. Fasting blood glucose, total cholesterol, triglyceride, high density lipoprotein-cholesterol(HDL-C), low density lipoprotein-cholesterol(LDL-C) and fasting insulin levels were tested after the model established. M-mode echocardiography was performed for echocardiographic measurements. The alteration of mTOR, p-mTOR, S6K1, Atg5 and P62 inmyocardium was determined by Western blotting. RESULTS Compared with control group, the level of total cholesterol, triglyceride and LDL-C significantly increased in 2 weeks and 4 weeks model group, while HDL-C were significantly reduced. The level of fasting blood glucose was normal in the semaglutide group, and the levels of HDL-C increased (P<0.05) while the level of LDL-C decreased significantly(P<0.01). The expression of mTOR, p-mTOR and S6K1 were continuously increased in 2 weeks and 4 weeks model group compared with control (p<0.01), and SEM intervention group declined showed by western blotting. The expression of Atg5 and p62 were also increased consistently in model group with the duration of the development in diatetic rats, while the semaglutide group showed the decreased tread. CONCLUSION In the early stages of the development of diabetic cardiomyopathy, the intervention of semaglutide may suppress the expression of mTOR signaling pathways and eventually decrease the occurrence of autophagy in myocardial cells.