基于气血理论从PINK1/Parkin通路探讨“益气活血”法调控线粒体自噬在心肌能量代谢重构中的作用

Cardiomyocyte damage is the beginning and ending of many heart diseases. In the damaged cardiomyocytes, the occurrence of metabolic remodeling and structural remodeling are the main cause of the damage. The imbalance of mitochondrial autophagy in damaged myocardium induced "energy starvation" or "oxidative stress", which plays a key role in cardiomyocyte metabolic remodeling. Based on the “Benefiting qi and activating blood circulation” method, Qishenyiqi have a positive effects on cardiomyocyte protection in many clinical studies. However, whether the mechanism involves in mitochondrial autophagy and metabolic remodeling remain unclear. Our study have both in vivo and in vitro part, use metabolic remodeling mice model and primary myocardial injury model. The mitochondrial autophagy mechanism mediated by PINK1/Parkin pathway was explored from the observation of mitochondrial autophagy, ATPase activity, ROS production, cardiomyocyte apoptosis and so on. The intervention effect of Qishenqiqi and its monomer also need observe.

心肌细胞受损是诸多心脏疾病的起始与终归。受损心肌细胞发生能量代谢障碍并重构是其受损的关键。受损心肌中的线粒体自噬失控，过度或不足分别导致的心肌细胞“能量饥饿”和“氧化应激”是发生心肌细胞代谢重构的关键。基于“益气活血”法指导下的芪参益气方在临床上对受损心肌具有肯定的保护作用，其机制是否涉及维持线粒体自噬稳态，改善心肌能量代谢重构是值得研究的科学问题。本研究拟采用在体实验和离体实验相结合的方法，以压力超负荷小鼠代谢重构模型以及原代心肌损伤模型为研究对象，从经典的PINK1/Parkin信号通路为切入点，从心肌细胞线粒体自噬现象的观察、ATP酶活力测定、ROS的产生、心肌细胞凋亡等诸多角度探索该途径介导的线粒体自噬平衡的机制以及芪参益气方及其有效单体的干预作用。

心肌能量代谢重构是多种心血管疾病的病理基础。在受损心肌细胞中，过度的线粒体自噬导致心肌细胞 “能量饥饿”，而自噬不足则导致细胞“氧化应激”。线粒体自噬过程平衡心肌细胞“能量饥饿”和“氧化应激”是调控受损心肌代谢重构的关键。“益气活血”法理论指导下的芪参益气方在临床上取得了一定的疗效。本研究以心肌细胞能量代谢重构为切入点，以缺血性心肌损伤SD大鼠为研究对象，从大鼠心脏结构、心功能、心肌纤维化、能量代谢、线粒体动力学等角度探讨益气活血法的作用及其作用机制，明确了益气活血法对缺血性心肌损伤大鼠的心功能影响作用。并从经典的PINK1/Parkin信号通路为切入点，从心肌细胞线粒体自噬现象的观察、ATP酶活力测定、ROS的产生、心肌细胞凋亡等诸多角度探索该途径介导的线粒体自噬平衡的机制以及益气活血法及其单体的干预作用。