Ang1-7对心肌肥厚电生理重构的干预研究

Angiotensin converting enzyme 2(ACE2), which was discovered in recent years, and its product, angiotensin1-7(Ang1-7), are critical parts of renin-angiotensin system (RAS) with functions as opposed to ACE and AngiotensinⅡ(AngⅡ). Our previous studies showed that the expression of ACE is increased and ACE2 decreased in the myocardium of spontaneously hypertensive rats(SHR). Adult SHR can be used as ideal animal model of myocardial hypertrophy, due especially to its presentation of marked myocardial hypertrophy. It has been known that a variety of electrophysiological abnormalities could be developed secondary to myocardial hypertrophy, leading to the occrences of certain arrhythmias, such as premature ventricular complex, ventricular tachycardia and even ventricular fribrillation. To date, however, few studies exists on both the cardiac electrophysiological remodeling and the effects of Ang1-7 on this remodeling. In this project, adult SHRs are going to be used as animal model of myocardial hypertrophy, and treated with Ang1-7. Four weeks later, the myocytes in epicardium and endocardium and M cells in midcardium will be isolated, and action potential (AP), resting potential(RP), peak sodium current(INa-T), later sodium current (INa-L), and L-type calcium current (ICa-L) measured using technologies of microelectrode and patch clamp, in order to reveal the characteristics of cardiac electrophysiological remodeling in myocardial hypertrophy, explore the effects of Ang1-7 on this remodeling, which will be helpful in exploring new treatment approach for the cardiac arrhythmias of hypertrophic myocardium.

血管紧张素转换酶2(ACE2)及其产物血管紧张素1-7(Ang1-7)是近年发现的肾素-血管紧张素系统(RAS)的重要成分，具有拮抗ACE及血管紧张素Ⅱ(AngⅡ)的作用。我们前期研究表明自发性高血压大鼠(SHR)心肌ACE升高、ACE2降低。成年SHR心肌明显肥厚，是肥厚心肌的理想动物模型。已知肥厚心肌易出现各种电生理学异常，导致心律失常如室早、室速乃至室颤的发生，然目前鲜有研究系统探讨肥厚心肌电生理重构及Ang1-7干预的影响。本课题以SHR心肌作为肥厚心肌模型，予Ang1-7干预，用微电极和膜片钳技术检测左心室内膜、外膜心肌细胞及中层M细胞的动作电位(AP)、静息电位(RP)、快钠电流(INa-T)、晚钠电流(INa-L)、L型钙电流(ICa-L)，以较为系统地揭示肥厚心肌电生理重构的特点，及Ang1-7的作用，丰富肥厚心肌的电生理研究，并为肥厚心肌心律失常的防治提供新的思路和方法。

背景：血管紧张素转换酶2(angiotensin-converting enzyme 2, ACE2)及其产物血管紧张素1-7(angiotensin 1-7, Ang1-7)是近年发现的肾素-血管紧张素系统(renin-angiotensin system, RAS)的重要成分，具有降压、改善内皮功能、抗炎和维持炎症因子网络平衡、抗心肌纤维化等多种功能。我们前期研究表明自发性高血压大鼠(spontaneous hypertensive rats, SHR)心肌ACE升高、ACE2降低。已知肥厚心肌易出现各种电生理学异常，导致心律失常如室早、室速乃至室颤的发生，然目前鲜有研究系统探讨肥厚心肌电生理重构及Ang1-7干预的影响。主要研究内容：以超声心动图作为主要手段，评价了SHR大鼠肥厚心肌的机械重构，并分离获取左心室肌细胞，应用微电机技术及膜片钳技术检测其动作电位、静息电位、离子通道电流，并与对照品系WKY大鼠相比较。然后以Ang1-7对SHR大鼠和WKY大鼠进行干预，之后评价心肌肥厚的变化，并分离获取心肌细胞，检测上述电生理指标和参数的变化，阐述Ang1-7对肥厚心肌电生理重构的逆转作用。关键数据和重要结果：Ang1-7干预后SHR大鼠收缩压、舒张压、平均动脉压均显著下降（154±14 mmHg vs 180±17mmHg，P＜0.05；81±12mmHg vs 114±12mmHg，P＜0.05；105±12mmHg vs 136±14mmHg，P＜0.05）；PWd、IVSd和LVM下降（1.75±0.29mm vs 1.94±0.30mm，P＜0.05；1.87±0.19mm vs 2.02±0.31mm，P＜0.05；929±82mm vs 995±80mm；P＜0.05）；FS升高(34±5mm vs 29±5mm，P＜0.05）；AP振幅、Vmax升高（-79±3mV vs -70±4mV，P＜0.05；412±43 V/s vs 382±37V/s，P＜0.05），APD20、APD50、APD90均缩短（9±4ms vs16±2ms，P＜0.05；16±4 ms vs 26±7ms，P＜0.05；90±11 ms vs 133±14ms，P＜0.05）；INa-T峰值电流升高（3225±376 pA vs 2945±382 pA，P＜0.05）