从miR-24介导Bim/caspase凋亡信号通路探讨益气逐瘀方干预心肌缺血细胞损伤的分子机制

The main pathophysiological process of coronary heart disease (CHD) is myocardium ischemia. Cell apoptosis is an important pathological mechanisms involved in early stage of myocardial ischemia. Recent studies revealed that miR-24, which is highly expressed in myocardial tissues, could protect myocardium ischemia by regulating the downstream Bim/caspase apoptosis signal pathway. Our previous studies have shown that, Shenyuan Yiqihuoxue Tang (SYT), a Chinese herbal formula developed based on the therapeutic principle of supplementing qi and pursuing stasis, could relieve ischemia and up-regulate miR-24 expression in myocardial infarction rats. Therefore, we assumed that whether SYT could protect myocardial ischemia by regulating miR-24 induced apoptosis signal pathway？ Based on the above, this study is designed to investigate the effects and molecular mechanisms of SYT on myocardial ischemia induced apoptosis through testing the gene and protein expression of miR-24 and its downstream key cellular factors in early stage of myocardial ischemia by establishing an in vivo myocardial ischemia rat model and an in vitro hypoxia cardiomyocyte model. The study will provide the new scientific basis for treatment of CHD based on the therapeutic principle of supplementing qi and pursuing stasis. It also offers the new ideas and new drug targets to the treatment of CHD.

冠心病发病的主要病理过程是心肌缺血，细胞凋亡是缺血早期细胞损伤的重要病理机制。近来研究表明，miR-24在心肌组织中高表达，并且能够通过调控下游Bim/caspase凋亡信号通路发挥心肌保护作用。课题组前期研究发现，基于益气逐瘀法组方的参元益气活血汤具有减轻心梗大鼠心肌损伤程度，上调缺血心肌组织miR-24表达的作用，然而其通过干预miR-24介导的下游Bim/caspase信号通路发挥心肌保护作用的具体作用机制尚不清楚。为此，本研究拟建立在体大鼠心肌缺血和离体乳鼠心肌细胞缺氧模型，通过检测miR-24及其下游Bim/caspase细胞凋亡信号通路关键细胞因子基因和蛋白表达，揭示参元益气活血汤抗心肌缺血细胞凋亡、抑减轻心肌损伤的分子机制。该研究可为益气逐瘀法防治冠心病提供新的实验依据，也为临床上探寻冠心病新的治疗方法和药物靶点提供思路。

冠心病发病的主要病理过程是心肌缺血，细胞凋亡是缺血早期细胞损伤的重要病理机制。研究表明，miR-24在心肌组织中高表达，并且能够通过调控下游Bim/caspase凋亡信号通路发挥心肌保护作用。课题组前期研究发现，基于益气逐瘀法组方的参元益气活血汤（SYD）具有减轻心梗大鼠心肌损伤严重程度，上调缺血心肌组织miR-24表达的作用，然而其通过干预miR-24介导的下游Bim/caspase信号通路发挥心肌保护作用的具体机制尚不清楚。本研究建立了在体大鼠心肌缺血和离体乳鼠心肌细胞缺氧模型，通过对心肌缺血缺氧过程中心肌损伤严重程度、心脏功能、细胞凋亡水平以及miR-24介导的Bim/caspase线粒体细胞凋亡信号通路关键细胞因子基因和蛋白表达的变化分析，揭示了miR-24通过调控Bim/caspase线粒体细胞凋亡信号通路干预细胞凋亡的作用及其机制，初步证实了SYD可能通过上调miR-24的表达，抑制线粒体细胞凋亡信号通路的激活减轻心肌缺血细胞凋亡，发挥心肌保护作用的分子机制。本研究将为益气逐瘀法在冠心病心肌缺血中的应用提供实验依据，也为临床上探寻冠心病新的治疗方法和药物靶点提供思路，将对拓展中医药在我国冠心病防治体系中的应用具有重要现实意义。