基于Apelin-AKT信号调节通路的参附注射液对急性心肌梗死泵衰竭作用的影响

Myocardial ischemia and hypoxia is one of the most common pathological state in cardiovascular disease, which caused the myocardial cell apoptosis and necrosis became the dominant factor in the development of heart failure (CHF). How to improve the cardiac pump function of the myocardial ischemia is a hotspot in research of cardiovascular. The project combined with the early fund project "Shenfu compatibility effects of poison" which based on the study of "ischemia hypoxia-abnormal energy metabolism of cells – cytokines changes - apoptosis-heart failure". To explore the mechanism of the Shenfu injection on acute myocardial ischemia action of pump failure with the apelin/PI3K/AKT signal pathway, to explore the cellular signal transduction mechanism of Shenfu injection against acute myocardial ischemia of pump failure. In order to clarify the mechanism of Shenfu injection against acute myocardial ischemia, finding an effective way of traditional Chinese medicine compound treatment for saving ischemia and dying myocardium, providing theoretical and experimental support.

心肌缺血、缺氧是心血管疾病中常见的病理状态之一, 其所致的心肌细胞凋亡、坏死等成为心力衰竭(CHF) 发生发展的主导因素, 因此如何提高心肌急性缺血（心肌梗死）后心脏的泵血功能始终是心血管领域研究的热点。本项目结合前期基金项目:"参附配伍量效毒关系"研究基础上，围绕“缺血缺氧-细胞能量代谢异常-细胞因子变化-细胞凋亡-心衰”这一关键环节，考察参附注射液对急性心肌缺血后泵衰竭的作用机制；继而围绕“apelin/PI3K/AKT”信号通路，探讨参附注射液抗急性心肌缺血后泵衰竭的细胞信号转导机制。以期阐明参附注射液抗急性心肌缺血的作用机制，从而为挽救缺血、濒死的心肌寻找一条有效的中药复方治疗途径提供理论和实验支持。

本项目采用结扎左冠状动脉的方法使其造成缺血，缺血时间30分钟再灌时间2小时和低氧低糖的方式建立大鼠急性心肌缺血动物模型和细胞模型，给予参附注射液治疗后，研究Apelin/APJ系统在心肌缺血不同时相表达的变化及心脏功能变化情况，分析参附注射液对内源性Apelin表达的影响，并考察了该作用与凋亡通路相关蛋白的关系及对心肌细胞能量代谢的干预作用，结果显示模型组中Apelin的表达量下降，参附注射液低药组、中药组、高药组相对于模型组Apelin、APJ、ERK1/2、P70s6k的表达上升。综合体内外实验蛋白活性、定量和基因表达变化结果揭示参附注射液能够提高心肌缺血再灌注损伤造成的apelin表达降低，改善缺血心肌血管收缩功能，通过ERK1/2信号通路，上调基因APJ、MEK1/2、ERK1/2、P70s6k来调控细胞增殖，抑制心肌细胞凋亡，从而对心肌缺血再灌注损伤造成的急性心衰起到治疗作用。本研究结果表明参附注射液在心衰时通过调控Apelin-APJ-ERK1/2-P70s6k信号通路来抑制心肌细胞凋亡从而起到保护心肌的作用，为降低缺血再灌注损伤所致的急性心衰提供实验依据。