尾加压素Ⅱ/氧化应激/内质网应激在糖尿病性心肌病心肌细胞凋亡中的作用及分子机制

Cardiomyocyte apoptosis is the major pathological change of diabetic cardiomyopathy, and also serves as the most important pathophysiological mechanism for diabetic cardiac dysfunction. Urotensin Ⅱ (UⅡ), currently known as the most powerful vasoconstrictor substances, has shown high expression level in diabetic myocardial tissue in our previous studies. It was also found that the endoplasmic reticulum stress (ERS)-induced cardiac myocyte apoptosis significantly increased in diabetic cardiomyopathy. Combined with the results from other research, we presumed that the UⅡ/oxidative stress(OS)/ERS pathway plays an important way in diabetic cardiomyopathy. This study will focus on the following area: ①The involvement of OS in the UⅡ-induced ERS and apoptosis in cultured cardiac myocyte. ②The role of UⅡ / OS / ERS pathway in diabetic metabolic abnormalities (high sugar, high free fatty acid)-induced cardiac myocyte apoptosis. ③The changes of cardiac function and myocardial tissue express of OS, the ERS and apoptosis after RNAi inhibition of UⅡ expression based on rats with type1 and type 2 diabetic cardiomyopathy, and the exploration of the role and molecular mechanisms of UⅡ in different types of diabetic cardiomyopathy. The results will help us to clarify the mechanism of diabetic cardiomyopathy, and will provide potential targets for the intervention of this disease.

心肌细胞凋亡是糖尿病性心肌病的主要病理改变，也是促进糖尿病心功能障碍的重要机制。尾加压素Ⅱ(urotensin Ⅱ, UⅡ)作为最强缩血管物质，在我们的研究中被证实高表达于糖尿病心肌组织。我们的研究还发现，内质网应激（endoplasmic reticulum stress，ERS）诱导的心肌细胞凋亡在糖尿病性心肌病中明显增加。本项目综合国内外研究现状，提出UⅡ/氧化应激/ERS通路是糖尿病心肌病重要分子机制的假说。本项目拟进一步研究：①体外培养心肌细胞，探讨氧化应激在UⅡ诱导心肌细胞ERS及凋亡中的作用；探讨UⅡ/氧化应激/ERS在高糖、高游离脂肪酸诱导心肌细胞凋亡中的作用；②以1型、2型糖尿病心肌病大鼠模型为研究对象，研究RNAi抑制UⅡ后，大鼠心功能及心肌组织氧化应激、ERS及凋亡的变化。研究结果将为阐明糖尿病心肌病的发生机制提供新的理论依据，为糖尿病心肌病的干预提供潜在靶点。

糖尿病性心肌病（diabetic cardiomyopathy，DCM）是诱导或加速糖尿病患者死亡的重要原因之一。我们针对DCM的发生机制进行了深入研究。首先，糖尿病性心肌病时尾加压素Ⅱ(urotensin Ⅱ, UⅡ)及其受体表达明显增高，而UⅡ具有明显的促心脏重构作用。我们在体外研究中证实UⅡ可以通过氧化应激(oxidative stress,OS)、内质网应激（endoplasmic reticulum stress，ERS）通路，参与并调控心肌细胞凋亡，在心肌细胞凋亡中发挥重要作用；并在体内及体外实验中证实，高糖环境和DCM时均可以促进UⅡ及其受体的表达，通过激活OS通路，启动了ERS通路，进而促进心肌细胞凋亡，从而证实UⅡ/OS/ERS途径在DCM大鼠心肌细胞凋亡中的作用及分子机制。本项目加深了对DCM发病机理的认识，并为糖尿病并发症的防治开拓了新的靶点。