ACE2-Ang-(1-7)轴在心肌缺血再灌注损伤中的作用及其机制研究

Despite of the protective role of ACE2 and Ang-(1-7) by counteracting the effect of angiotensin II, the effect of ACE2-Ang-(1-7) axis on myocardial ischemia and reperfusion (I/R) injury is still unclear. Furthermore, the combinatory effect of ACE2/Ang-(1-7) and ACEI or ARB is also to be determined. Our preliminary results have demonstrated that ACE2-Ang-(1-7) axis plays an important role during myocardial I/R injury. Furthermore, our rencent study found that combinatory use of Ang-(1-7) and ACEI/ARB is superior to separate treatment for atherosclerosis and diabetic cardiomyopathy. To investigate the role and the mechanism of ACE2-Ang-(1-7) axis in the pathogenesis of the myocardial I/R injury, the present study was designed to examine the effects of exogenous ACE2 overexpression, ACE2 gene knockout,exogenous Ang-(1-7) overexpression, AT2R gene knockout, Mas receptor gene knockout and ARB on myocardial I/R injury in vivo and in vitro, and the corresponding signaling pathways will also be compared Furthermore, we also compare the protective effect of combinatory and separate treatments on myocardial I/R injury.This study will result in a better understanding of the mechanism in the pathogenesis of myocardial I/R injury in the levels of molecules, cells, tissues and animals, and provide a novel target for myocardial I/R prevention and treatment.

ACE2-Ang-(1-7)轴与心肌缺血再灌注（I/R）损伤的关系及ACE2/Ang-(1-7)联合ACEI/ARB是否优于单药治疗目前尚不明确。我们预实验提示ACE2-Ang-(1-7)在心肌I/R发生中起重要作用，但其具体作用机制还有待进一步探讨。前期研究发现联合应用Ang-(1-7)和ACEI/ARB对于动脉粥样硬化和糖尿病心肌病效果优于单药治疗。为阐明ACE2-Ang-(1-7)轴在心肌I/R损伤发病和干预中的作用及其分子机制，本课题拟通过构建小鼠心肌I/R损伤的体内和体外模型，采用基因敲除、RNA干扰等手段，探讨ACE2-Ang-(1-7)轴在心肌I/R损伤中的作用，明确ACE2-Ang-(1-7)调控心肌I/R损伤的机制，同时对比联合用药及单药治疗的效果。本研究将从ACE2-Ang-(1-7)轴这个新视点揭示心肌I//R损伤的发生机制，为心肌I/R损伤的防治提供新靶点。

RAS过度激活是心肌缺血再灌注损伤的关键因素之一。近年来的研究发现ACE2-Ang-(1-7)轴可有效拮抗过度激活的RAS发挥心血管保护作用。心肌缺血再灌注损伤发病机制复杂，ACE2-Ang-(1-7)能否在心肌缺血再灌注损伤中发挥保护作用目前尚不明确。本课题探索了ACE2-Ang-(1-7)在心肌缺血再灌注损伤中的作用及其调控机制。结果表明，心肌缺血再灌注明显激活RAS，升高血管紧张素II水平。ACE2、Ang-(1-7)和氯沙坦干预减少心肌梗死范围，与单药治疗相比，ACE2+氯沙坦和Ang-(1-7) +氯沙坦更进一步减少心肌梗死范围。其机制与增加ACE2/ACE比值，维持RAS平衡，降低炎症反应，减少心肌细胞凋亡有关。然后我们又通过缺氧复氧模型，在细胞水平证实了ACE2、Ang-(1-7)和氯沙坦对心肌细胞的保护作用。本课题首次揭示了ACE2-Ang-(1-7)轴及其与氯沙坦联合用药在心肌缺血再灌注损伤中的作用及分子机制，并为疾病的防治提供了新的靶点，具有重要的理论意义和潜在的临床应用价值。