肥胖所致心肌重构是心衰发生发展的重要危险因素，线粒体对维持心脏功能和代谢具关键作用。我们前期研究发现增强迷走活性能改善高血脂大鼠心脏功能，但迷走神经如何调控肥胖所致心肌重构及线粒体机制尚不清。本项目拟建立肥胖诱导心肌重构模型结合检测迷走活性并给予拟胆碱药物等干预：①用微透析和免疫组化等方法观察脂毒性及线粒体氧化损伤对心肌重构的影响及迷走对脂肪表型转化的调控；②探讨迷走调控肥胖所致心肌重构的线粒体稳态机制，包括：a)用siRNA和免疫共沉淀等检测线粒体动力学和嵴塑形蛋白Drp1、OPA1和mitofilin/Mic10/Sam50复合物变化，探究迷走调节线粒体结构稳态的药靶；b)用重亚硫酸盐测序、气-质联用、免疫共沉淀等技术检测DNA甲基化、mtUPR和线粒体-内质网交互，探讨迷走调节线粒体功能稳态的信号通路。本项目有望为防治代谢性心血管病提供新药理学干预措施和线粒体药物靶点。

Cardiac remodeling induced by obesity is the important risk factor in heart failure. Mitochondrial homeostasis is of great significance for preserving cardiac function and metabolic balance，which might related to cardiac remodeling. Our previous study indicated that the cardiac function of hyperlipidemia rats could be improved by enhancing vagal activity, but there is not yet systematic mechanism study about link of vagal regulation with mitochondrial homeostasis and cardiac remodeling induced by obesity. This project will establish cardiac remodeling induced by obesity combined with vagal nerve measurement and cholinergic drug intervention to: 1. investigate the effect of vagal nerve on epicardial fat phenotype transformation and lipotoxicity induced mitochondrial oxidative damage in cardiac remodeling by using microdialysis and immunohistochemistry; 2.disclose the effect of vagal nerve on mitochondrial homeostasis in cardiac remodeling model induced by obesity and related signal pathway. We are going to a) explore the effect of cholinergic drug on mitochondrial shaping proteins Drp1, OPA1 and mitofilin/Mic10/Sam50 complex by co-immunoprecipitation and siRNA and further clarify the effect of mitochondrial dynamics and cristae remodeling on cardiac mitochondrial structure homeostasis. b) measure the effect of DNA methylation, mtUPR and mitochondrial-endoplasmic reticulum interactions on cardiac mitochondrial function homeostasis signal pathway by bisulfite sequencing, gas chromatograph-mass spectrometer and Co-immunoprecipitation. Our study may provide pharmacological interventions targeting on anti-metabolic cardiovascular disease and explore new mitochondria-related drug targets.