基于ACE-AngII轴和ACE2-Ang(1-7)轴的失衡探讨通冠胶囊改善心梗后心室重构的机制研究

Myocardial infarction is a serious disease to human health, and myocardial fibrosis is the key mechanism of the ventricular remodeling with myocardial infarction. Previous studies found that the traditional chinese medicine of supplementing Qi and activating blood circulation, Tongguan Capsule not only inhibited myocardial fibrosis, but also improved cardiac function and left ventricular remodeling induced by myocardial infarction, nevertheless the mechanism remains unclear. Recent studies found that the ACE-Ang II-AT1R axis of RAS system promoted while the ACE2-Ang (1-7) -Mas axis inhibited the myocardial fibrosis induced by myocardial infarction. As the cardiac fibrosis and ventricular remodeling was induced by the imbalance of ACE-Ang II -AT1R axis and ACE2-Ang (1-7) -Mas axis in heart RAS system.The balance of ACE-Ang II -AT1R axis and ACE2-Ang (1-7) -Mas axis is good for the inhibitory of myocardial fibrosis and ventricular remodeling with myocardial infarction.Thus, we speculate that Tongguan Capsule may inhibited the collagen synthesis of cardiac fibroblast in ventricular remodeling induced by myocardial infarction, through inhibit the NOX2-ROS-RhoA-Rock signal pathway by restoring the ACE-AngII-AT1R axis and ACE2-Ang (1-7) -Mas axis balance.The research may provide a traditional chinese theory of supplementing Qi and activating blood circulation method for the ventricular remodeling with myocardial infarction. Furthermore, the research can provide new ideas and new target for the prevention and treatment of ventricular remodeling with myocardial infarction.

心肌梗死是严重危害人类健康的重要疾病，心梗后心肌纤维化(MF)是心梗后心室重构的关键。前期研究发现，益气活血中药通冠胶囊具有抑制心梗后MF，改善心梗后心功能和左室重构的作用，但其机制尚未明确。新近研究发现心脏RAS系统的ACE-AngⅡ-AT1R轴促进而ACE2-Ang(1-7)-Mas轴抑制心梗后MF；正由于心梗后RAS系统的ACE-AngⅡ-AT1R轴和ACE2-Ang(1-7)-Mas轴发生失衡，心脏发生纤维化和心室重构。因此，恢复RAS系统的平衡对改善心梗后MF和心室重构意义重大。由此，我们设想通冠胶囊通过恢复ACE-AngII-AT1R轴和ACE2-Ang(1-7)-Mas轴的平衡，进而抑制NOX2-ROS-RhoA-Rock信号通路，减少心肌成纤维细胞胶原的合成，最终抑制心梗后心室重构；为心梗后心室重构“气虚血瘀”理论提供依据；为心梗后心室重构的防治提供新思路和药物作用新靶点。

背景：心肌梗死是严重危害人类健康的重要疾病，心梗后心肌纤维化是心梗后心室重构的关键。前期研究发现，益气活血中药通冠胶囊具有抑制心梗后心肌纤维化，改善心梗后心功能和左室重构的作用，但其机制尚未明确。新近研究发现正由于心梗后RAS系统的ACE-AngⅡ-AT1R轴和ACE2-Ang(1-7)-Mas轴发生失衡，心脏发生纤维化和心室重构。.研究内容：采用SD大鼠建立结扎冠状动脉左前降支的急性心肌梗死后心室重构模型，进行分组并运用小动物超声检测评估大鼠心脏形态及功能变化，并进行心脏病理和心肌纤维化的观察。通过检测胶原蛋白（collagen）的表达情况，检测各实验组血清和心脏组织中AngⅡ和Ang(1-7)的含量及氧化应激通路相关蛋白的表达水平来综合评估大鼠心肌纤维化和心室重构情况。体外细胞实验观察AngⅡ是否通过激活NOX2-ROS-Rock2通路促进成纤维细胞合成胶原，最后观察通冠胶囊对AngII刺激的ACE2siRNA心肌成纤维细胞胶原合成的影响及机制。.结果：相比于对照组，通冠胶囊能够减少大鼠心肌梗死面积，降低心肌纤维化程度，改善心脏功能。通冠胶囊能够改善心肌细胞凋亡的情况，有效降低冠状动脉左前降支结扎后的collagen1蛋白表达量，能够使心肌纤维化的表达降低，同时还能使心肌梗死大鼠的血清和心肌细胞AngⅡ蛋白水平下调而Ang（1-7）蛋白水平发生明显上调（P<0.05），说明通冠胶囊能够产生双向调节的作用。在细胞水平上，通冠胶囊还能够有效降低NOX2、Rock2蛋白的表达水平，还能使心肌细胞ROS（H2O2）含量降低。也证明了当氧化应激通路被抑制后，AngⅡ有进一步加重心肌纤维化的情况，而通冠胶囊能够对ACE与ACE2轴进行双向调节，改善心肌梗死后心肌纤维化及心室重构的进程。.研究意义：实验数据表明益气活血中药通冠胶囊具有双向调节RAAS系统的作用，一方面抑制ACE-AngII-AT1R 轴，另一方面促进ACE2-Ang(1-7)-Mas轴的表达，从而抑制心肌细胞胶原蛋白的表达。其信号通路是通过NOX2-ROS-Rock2-Collagen的信号转导通路介导。本研究在中西医结合理论及方法方面具有一定的创新性，对心肌梗死的中西医结合治疗进行了有益的探索，提供了一定的理论依据。