基于AMPK激活的线粒体自噬通路探讨生脉饮抗心力衰竭的作用机制

Heart failure is one of the most severe diseases in the cardiovascular system. The abnormal myocardial mitophagy happens throughout the whole development of heart failure. The PINK1/Parkin-mediated mitophagy is a critical factor in decompensation of heart failure. AMPK can activate Pink1/Parkin-mediated mitophagy, improve mitochondrial function, energy metabolism, reduce ROS level and cardiomyocyte apoptosis. However, there is still a lack of effective drugs for this target. Shengmai Yin has been used to prevent and treat heart failure for many years. The research reports that Shengmai Yin and its related ingredients can improve the energy metabolism of heart failure and raise AMPK activity. Based on this, we proposed the hypothesis that “Shengmai Yin may activate Pink1/Parkin-mediated mitophagy to achieve its protective effect on heart failure heart function by regulating AMPK”. For the research, we are going to use the mouse models with transverse aortic constriction and intervention the models with Shengmai Yin. Echocardiography, confocal laser scanning, transmission electron microscopy and Western Blot will be used to study the whole body, tissue, cellular and molecular levels. At the end of the research, we expect to partially reveal the regulatory mechanism of Shengmai Yin on mitophagy in heart failure and provides scientific evidence for clinical heart failure treatment.

心力衰竭是心血管系统最为严重的病症之一。心肌细胞线粒体自噬异常贯穿心力衰竭发展始终。PINK1/Parkin介导的线粒体自噬能力下降是心力衰竭失代偿的关键因素。AMPK可通过激活线粒体自噬改善线粒体功能及能量代谢，降低ROS水平和心肌细胞的凋亡，缓解心力衰竭。但目前仍缺乏针对该靶点的有效药物。生脉饮能够有效治疗慢性心衰。研究证实生脉饮及其相关成分可改善心力衰竭能量代谢，并可上调AMPK活性。据此我们提出“生脉饮可能通过调节AMPK激活Pink1/Parkin介导的线粒体自噬达到其对心衰心功能的保护作用”的假说。拟采用压力负荷心衰模型，使用生脉饮进行干预，运用超声心动、激光共聚焦、透射电镜、Western Blot法等方法，从整体、组织、细胞、分子层面进行研究。以期部分揭示生脉饮对心力衰竭线粒体自噬的调控机制，为生脉饮防治心力衰竭提供科学依据。

心力衰竭是心血管系统最为严重的病症之一。心肌细胞线粒体自噬异常贯穿心力衰竭发展始终。PINK1/Parkin介导的线粒体自噬能力下降是心力衰竭失代偿的关键因素。AMPK可通过激活线粒体自噬改善线粒体功能及能量代谢，降低ROS水平和心肌细胞的凋亡，缓解心力衰竭。通过本研究，我们发现，生脉饮对慢性心力衰竭的心功能及心脏结构有保护作用，生脉饮可以有效改善慢性心力衰竭小鼠心肌细胞的凋亡，自噬与线粒体自噬。生脉饮可提高心力衰竭小鼠的ampka2水平，同时还存在对ampka1的抑制。生脉饮可调节心力衰竭小鼠心肌细胞PINK1/Parkin以及LC3和SQSTM1的蛋白表达水平。据此我们推测，生脉饮可能是通过调节AMPKα2水平激活的一般自噬及线粒体自噬通路发挥其抗心力衰竭作用。