Yamazato Yoriko, Ferreira Anderson J, Hong Kwon-Ho, Sriramula Srinivas, Francis Joseph, Yamazato Masanobu, Yuan Lihui, Bradford Chastity N, Shenoy Vinayak, Oh Suk P, Katovich Michael J, Raizada Mohan K
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610-0274, USA.
Hypertension. 2009 Aug;54(2):365-71. doi: 10.1161/HYPERTENSIONAHA.108.125468. Epub 2009 Jun 29.
In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25+/-1 mm Hg; MCT: 44+/-5 mm Hg; MCT+ACE2: 26+/-1 mm Hg; n=6; P<0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25+/-0.01; MCT: 0.31+/-0.01; MCT+ACE2: 0.26+/-0.01; n=8; P<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the angiotensin II type 2 receptor:angiotensin II type 1 receptor mRNA ratio. Also, pulmonary hypertension-induced increases in proinflammatory cytokines were significantly attenuated by lentiviral vector-containing ACE2 treatment. Furthermore, ACE2 gene transfer in mice after 6 weeks of MCT treatment resulted in a significant reversal of right ventricular systolic pressure. These observations demonstrate that ACE2 overexpression prevents and reverses right ventricular systolic pressure and associated pathophysiology in MCT-induced pulmonary hypertension by a mechanism involving a shift from the vasoconstrictive, proliferative, and fibrotic axes to the vasoprotective axis of the renin-angiotensin system and inhibition of proinflammatory cytokines.
尽管近年来肺动脉高压的治疗取得了进展，但仍未实现成功控制。肺中大量存在的血管紧张素转换酶2（ACE2）及其在预防急性肺损伤方面的显著效果，促使我们检验该酶在肺中过表达可能对肺动脉高压产生有益结果的假设。用野百合碱（MCT）处理小鼠8周导致右心室收缩压、右心室与左心室加室间隔重量比显著增加，以及肺血管肌化。在MCT处理前7天给予含ACE2的慢病毒载体可防止右心室收缩压升高（对照组：25±1 mmHg；MCT组：44±5 mmHg；MCT + ACE2组：26±1 mmHg；n = 6；P < 0.05）以及右心室与左心室加室间隔重量比升高（对照组：0.25±0.01；MCT组：0.31±0.01；MCT + ACE2组：0.26±0.01；n = 8；P < 0.05）。在过表达ACE2的动物中也观察到MCT诱导的肺血管肌化显著减轻。这些有益作用与2型血管紧张素受体与1型血管紧张素受体mRNA比值增加有关。此外，含ACE2的慢病毒载体处理可显著减轻肺动脉高压诱导的促炎细胞因子增加。此外，在MCT处理6周后对小鼠进行ACE2基因转移导致右心室收缩压显著逆转。这些观察结果表明，ACE2过表达通过涉及从肾素 - 血管紧张素系统的血管收缩、增殖和纤维化轴转变为血管保护轴以及抑制促炎细胞因子的机制，预防和逆转MCT诱导的肺动脉高压中的右心室收缩压及相关病理生理学变化。
