中枢血管紧张素系统ACE2/AT1平衡在运动训练阻止高血压前期进展中的作用

Compared with normal blood pressure, prehypertension more easily progress to hypertension and cardiovascular events. Exercise training delays the progression of prehypertension, but its mechanism has not been fully understood. Our previous study showed that exercise training (ExT) enhanced gene and protein expression of angiotensin converting enzyme 2(ACE2) and inhibited the protein expression of angiotensin II type 1 receptor (AT1) in the brain, which improved arterial baroreflex and reduced blood pressure in spontaneously hypertensive rats (SHR). However, the role of central ACE2 in exercise-induced fall in blood pressure and cardiac protection remains to be clarified. The present study was to investigate the effects of 8 , 16 and 32wk of treadmill running on blood pressure, baroreflex and cardiac function from 8-wk male SHR, detecting the changes of the gene and protein expression of ACE/ACE2, AT1/Mas receptors in the brain ( PVN, NTS) and in the cardiomyocytes. central ACE2 pathway was investigated by intravenous and intracerebroventricular treatment of agonist and antagonist of AT1/Mas receptors in the trained SHR. Furthermore, the effects of over-expression of ACE2 gene in the brain on AngII/Ang-(1-7) contents and gene and protein expression of AT1/Mas receptors in the cardiovascular centers as well as cardiac function were determined in the trained SHR. In the cultured neurons, effects of ACE2 gene overexpression on AngII-induced superoxide anions level and gene and protein expression of NADPH oxidase and nitric oxide synthase were also investigated. These results will provide the experimental evidence to account for cellular and molecular mechanisms of central ACE2 in the prevention of progression of hypertension induced by exercise training.

高血压前期较正常血压更易进展为高血压和心血管事件，运动训练能延缓高血压前期的进展，但机制未明。我们前期在自发性高血压大鼠（SHR）观察到运动训练能增强中枢血管紧张素转换酶2(ACE2)表达、抑制中枢血管紧张素II 1型受体（AT1）表达，改善动脉压力反射，产生降压作用。但中枢ACE2在运动降压和对心脏保护的作用尚待研究。本项目拟从8周SHR开始，观察8、16、32wk跑台运动对血压、压力反射和心脏功能的影响，检测心肌、中枢（室旁核、孤束核）ACE/ACE2,AT1/Mas表达变化，外周和中枢应用AT1/Mas受体激动剂和阻断剂以明确ACE2作用通路；中枢过表达ACE2基因对中枢AngII/Ang(1-7)、 AT1/Mas以及对心脏功能的影响；神经细胞过表达 ACE2基因对AngII诱导超氧阴离子、NADPH氧化酶和一氮化氮合酶表达的影响，以明确运动训练延缓高血压进程的细胞和分子机制。

运动训练在高血压防控中发挥重要作用，但机制尚未完全清楚。本项目研究有氧运动阻止高血压前期进展及其中枢机制。自发性高血压大鼠（SHR）从高血压前期（6周龄）开始进行8、16和20周中低强度跑台运动，结果显示：不同时程运动均显著推迟高血压发生、延缓高血压进展、改善动脉压力反射功能、减轻高血压所致心肌肥厚与纤维化、增强有氧运动能力和心脏功能。SHR大鼠心血管中枢 [延髓头端腹外侧（RVLM）、孤束核（NTS）和室旁核（PVN）] 血管紧张素转换酶（ACE）和血管紧张素II 1型受体（AT1）表达高于正常WKY大鼠，而ACE2和血管紧张素1-7受体（Mas）表达低于WKY大鼠，8-20周运动训练逆转这些改变。中枢给予血管紧张素II（AngII）或Mas受体阻断剂A779取消运动训练改善心血管活动的益处，相反，AT1受体阻断剂Losartan或血管紧张素1-7 （Ang1-7）增强运动训练的作用，提示运动训练延缓高血压进展与改善中枢ACE2-Ang1-7-Mas轴和ACE-AngII-AT1轴平衡有关。中枢（室旁核）过表达ACE2基因，降低SHR大鼠脑内AngII水平和AT1表达、升高Ang1-7和Mas表达，增强运动降压作用。在培养的neuro-2A神经细胞过表达ACE2 基因，降低AngII诱导超氧阴离子水平。由此得出结论：高血压前期运动训练延缓高血压进展和高血压相关的心脏病理改变，这一作用与运动训练改善心脏和中枢ACE2/ACE、Mas/AT1平衡有关,中枢ACE2过表达减轻细胞氧化应激可能是运动训练延缓高血压进展的分子机制。本研究表明，运动干预通过影响脑内和心脏血管紧张素系统ACE2/AT1平衡实现中枢降压和心脏保护作用。这一结果为有氧运动训练应用于心血管疾病的预防与康复提供实验证据。