ACE2-Ang-(1-7)-Mas轴在体-肺分流性肺动脉高压中的作用及机制研究

ACE2-Ang-(1-7)-Mas axis can significantly inhibit pulmonary vascular remodeling in drug-induced pulmonary hypertension.Our preliminary study showed that the level of serum ACE2 content and activity reduced in patients with severe pulmonary hypertension related to congenital heart disease,comparing to the patients with normal pulmonary arterial pressure, and the pulmonary arterial pressure was negatively correlated with the level of serum ACE2 content and activity,suggesting that ACE2-Ang-(1-7)-Mas axis may plays an important role in patients with pulmonary hypertension related to congenital heart disease. Through the carotid artery-jugular vein shunting surgery,we establish the model of pulmonary hypertension related to congenital heart disease induced by left-right shunt.This study will observe the changes of ACE2, Ang-(1-7) and Mas expression,and observe the effects of overexpression of ACE2 and Ang-(1-7) on pulmonary vascular remodeling, pulmonary artery pressure and MAPK signal transduction pathway in the model of shunt-induced pulmonary hypertension. This study will firstly investigate the effects and mechanisms of the ACE2-Ang-(1-7)-Mas axis on shunt-induced pulmonary hypertension, and partly contribute to awareness of the disease, and providing new theoretical basis and new therapeutic targets for prevention and treatment of shunt-induced pulmonary hypertension.

在药物诱导的肺动脉高压中，ACE2-Ang-(1-7)-Mas轴对于肺血管重构、肺动脉高压的发生、发展有着明显的抑制作用。我们的前期研究显示,先心病重度肺动脉高压患者中血清ACE2含量和活性水平较先心病正常肺动脉压患者明显降低，血清ACE2含量和活性水平与肺动脉压呈负相关，提示ACE2-Ang-(1-7)-Mas轴可能在先心病肺动脉高压中起着重要作用。本课题进一步在大鼠颈动、静脉之间建立体-肺分流，作为左向右分流先心病肺动脉高压的动物模型，观察ACE2、Ang-(1-7)、Mas的表达变化，及过表达ACE2、Ang-(1-7)对体-肺分流性肺动脉高压肺血管重构、肺动脉压力及MAPK信号转导通路的影响。本课题首次探讨ACE2-Ang-(1-7)-Mas轴在体-肺分流性肺动脉高压中的作用及机制，有利于促进对该疾病的认识,同时为该病的防治提供新的理论依据和新的治疗靶点。

在药物诱导的肺动脉高压中，ACE2-Ang-(1-7)-Mas轴对于肺血管重构、肺动脉高压的发生、发展有着明显的抑制作用。本课题拟观察ACE2-Ang-(1-7)-Mas轴在体-肺分流型肺动脉高压中的作用。我们应用套管法建立了大鼠颈动-静脉分流，术后抗凝、抗血小板治疗，但仍出现血管堵塞情况。应用兔子采用左侧颈总动脉-左侧颈外静脉端侧吻合的方式建立分流，但术后10周分流率低。我们在先天性心脏病肺动脉高压患者血清中，应用人ACE2、Ang-(1-7)-ELISA检测试剂盒检测ACE2、Ang-(1-7)含量水平、ACE2活性比色法定量检测试剂盒检测ACE2活性水平。发现，先天性心脏病重度肺动脉高压患者中血清ACE2、Ang-(1-7)含量和ACE2活性水平较先天性心脏病病正常肺动脉压患者明显降低，血清ACE2、Ang-(1-7)含量和ACE2活性水平与肺动脉压呈负相关；先天性心脏病肺动脉高压患者封堵术后Ang-(1-7)含量较术前升高。该研究结果有助于揭示先天性心脏病肺动脉高压的发病机制，有助于为研究降低先天性心脏病肺动脉高压药物提供新的靶点。我们应用套管法建立了大鼠颈动-静脉分流，术后抗凝、抗血小板治疗，但仍出现血管堵塞情况。应用兔子采用左侧颈总动脉-左侧颈外静脉端侧吻合的方式建立分流，但术后10周分流率低。我们在先天性心脏病肺动脉高压患者血清中，应用人ACE2、Ang-(1-7)-ELISA检测试剂盒检测ACE2、Ang-(1-7)含量水平、ACE2活性比色法定量检测试剂盒检测ACE2活性水平。发现，先天性心脏病重度肺动脉高压患者中血清ACE2、Ang-(1-7)含量和ACE2活性水平较先天性心脏病病正常肺动脉压患者明显降低，血清ACE2、Ang-(1-7)含量和ACE2活性水平与肺动脉压呈负相关；先天性心脏病肺动脉高压患者封堵术后Ang-(1-7)含量较术前升高。该研究结果有助于揭示先天性心脏病肺动脉高压的发病机制，有助于为研究降低先天性心脏病肺动脉高压药物提供新的靶点。