Notch3调控Mst1在糖尿病心肌病损伤中的作用及机制研究

Diabetic cardiomyopathy causes cardiac dysfunction, leading to clinical heart failure, cardiogenic shock, and even sudden death. However, there was still lack of efficient therapeutic methods in clinic. Recent studies revealed that Notch3 could significantly improve pathological heart function. However, whether Notch3 could reduce myocardial injury in diabetic cardiomyopathy has not been reported yet. Our previous study found that Mst1 knockout could promote autophagy and inhibit apoptosis in cardiomyocytes, and improve cardiac function in diabetic mice. Notch3 could also inhibit Mst1 expression and its phosphorylation. Combined with the analysis of preliminary experimental results, we propose that Notch3 may promote autophagy and inhibit apoptosis by inhibiting the expression and phosphorylation of Mst1 in cardiomyocytes, thereby inhibiting the occurrence and development of diabetic cardiomyopathy. The purpose of this project is to explore the role of Notch3/Mst1 signaling pathway in diabetic cardiomyopathy and its molecular mechanism, which is expected to provide new ideas and experimental basis for the prevention and treatment of diabetic cardiomyopathy.

糖尿病心肌病引起心脏功能障碍，导致临床心力衰竭，心源性休克，甚至猝死。然而，临床上缺乏有效的治疗方法。近年研究显示，Notch3能明显改善病理性心脏心功能，但Notch3是否能够减轻糖尿病心肌病心肌损伤，目前还未见相关报道。我们前期研究发现，敲除Mst1能够促进心肌细胞自噬，抑制凋亡，改善糖尿病小鼠心功能；同时，Notch3能够靶向抑制Mst1表达及其磷酸化。结合预实验结果分析，我们提出Notch3可能通过抑制心肌细胞Mst1的表达及其磷酸化，进而促进心肌细胞自噬，抑制凋亡，从而抑制糖尿病心肌病的发生发展。本项目旨在探讨Notch3/Mst1信号通路在糖尿病心肌病中的作用及其分子机制，有望为糖尿病心肌病的防治提供新的思路和实验依据。

糖尿病心肌病引起心脏功能障碍，导致临床心力衰竭，心源性休克，甚至猝死。然而，临床上缺乏有效的治疗方法。阐明糖尿病心肌病心肌损伤机制及保护策略是心血管领域中亟待解决的关键科学问题。课题组前期研究发现Notch3降低心脏缺血再灌注后梗死面积，改善线粒体损伤，改善心功能不全，Mst1敲除降低心肌细胞凋亡，改善糖尿病心肌病小鼠心功能。本课题组提出如下假说：Notch3通过调节Mst1改善线粒体损伤，减少细胞凋亡，从而改善糖尿病小鼠心功能障碍。本课题组按照课题规划，分别用敲除与过表达Notch3转基因小鼠和Mst1基因敲除小鼠构建糖尿病心肌病模型以及Notch3敲除及过表达病毒和Mst1敲除病毒，在动物及细胞层面分别证实了课题假说的内容。Notch3降低糖尿病小鼠心肌氧化应激和心肌纤维化，凋亡水平，从而改善心功能障碍。此外，通过对各组小鼠进行转录组测序，发现Notch3通过调节PPARα在糖尿病心肌病中发挥作用。本研究立足于改善糖尿病心肌病心功能障碍，系统研究了Notch3在糖尿病心肌病中发挥的作用，阐明Notch3对糖尿病心肌病心肌的保护机制，为临床糖尿病心肌病患者的治疗提供了新的治疗靶点。