FSTL1/SIRT1信号通路在糖尿病心肌病的保护机制研究

Diabetic cardiomyopathy is one of the most common complications due to diabetes mellitus with a complex pathological mechanism. The overall metabolic dysfunction caused by diabetes mellitus resulted in the disturbance of homeostasis of cytokines in the circulation system, which is a main factor of diabetic cardiomyopathy. Numerous studies have revealed that FSTL1 has a protection role against cardiac injury through regulating multiple signal molecules in myocardium. Sustained supply of recombinant FSTL1 can attenuate MI injury by promoting cardiac regeneration. In our previous study, FSTL1 was discovered to display a protective role against the high-fat and high-glucose induced cardiomyocytes apoptosis in vitro. However， the precise molecular mechanism that FSTL1 can protect cardiomyocytes from injury induced by high fat. The project is designed to study the protective role of FSTL1 either by inhibition or by activation on diabetic cardiomyopathy by in vitro and in vivo mouse models. The study will discover the key signal molecules and reveal the potential mechanism of FSTL1 mediated protection against diabetic cardiomyopathy. Our research will provide a novel target against diabetic cardiomyopathy with theoretical basis and clinical use.

糖尿病心肌病已经成为糖尿病最为常见的并发症之一，病理机制复杂。由糖尿病机体代谢紊乱诱发的循环系统细胞外分泌功能性细胞因子的稳态失衡是糖尿病心肌病发病的重要因素。众多研究表明分泌性FSTL1蛋白能够调控心肌细胞多种信号通路达到对抗心肌损伤保护心肌的作用。持续给予重组的FSTL1能够减轻心梗损伤，促进心脏的再生。我们前期的研究发现，FSTL1作为一种循环系统的心肌保护细胞因子具有明确的减轻高糖高脂所致的心肌细胞凋亡的作用。然而，FSTL1调控下游信号分子对抗糖尿病心肌损伤的具体分子机制仍不明确。本研究拟通过离体和在体糖尿病心肌病模型，通过给予外源性FSTL1或抑制内源性FSTL1，研究其对糖尿病心肌病的作用，寻找下有关键信号分子，揭示FSTL1对抗糖尿病心肌病的分子保护机制，探讨FSTL1及其下游信号通路作为糖尿病心肌病的作用靶点提供理论基础和潜在临床价值。

糖尿病已经成为全世界最主要的慢性疾病，而心血管并发症是其最主要的并发症。然而糖尿病心肌病的发病机制仍未完全阐明。FSTL1（卵泡抑素样蛋白1）是一种内源性分泌蛋白，前人众多研究发现它具有减轻心肌损伤和保护心脏的功能。该研究利用SIRT1敲除小鼠和构建2型糖尿病模型，试图阐明FSTL1保护糖尿病心肌病的作用分子机制。经过3年的研究，我们发现：1）给予重组FSTL1能提高糖尿病损伤的左室射血分数和短轴缩短率，降低心肌纤维化，改善心功能。2）利用SIRT敲除鼠，我们还发现，FSTL1的保护作用是通过激活SIRT1信号通路和下游的PGC-1a信号，对抗心肌氧化损伤和心肌细胞凋亡。3）通过离体实验我们验证了SIRT1和PGC-1a是FSTL1发挥保护作用的关键分子。4）此外，我们还研究了内源性小分子物质褪黑素对糖尿病心梗损伤的保护作用及其具体的分子机制。我们发现，褪黑素能够抑制JNK/p53信号通路，减轻糖尿病心梗损伤导致的心肌细胞凋亡。该研究的成果为临床治疗糖尿病心血管并发症提供了理论依据。