Role of angiotensin-converting enzyme 2 in cardiac hypertrophy induced by nitric oxide synthase inhibition

Objective Angiotensin-converting enzyme 2 (ACE2) generates angiotensin-(1-7) [Ang-(1-7)], a peptide highlighted as exerting a pivotal role in cardiovascular remodeling. Moreover, the ACE2/Ang-(1-7)/Mas axis directly activates endothelial nitric oxide (NO) synthase and NO generation in the heart. However, the role of ACE2 in cardiovascular remodeling induced by persistent inhibition of NO under chronic activation of the renin-angiotensin system (RAS) remains poorly understood. Methods and results Chimeric hypertensive mice that exhibit activation of the human RAS were produced by mating human renin (hRN) and human angiotensinogen (hANG) transgenic mice. Persistent NO inhibition with N-G-nitro-L-arginine methyl ester (L-NAME) was started at 8 weeks of age for 4 weeks. After administration of L-NAME, blood pressure (BP) markedly increased in the chimeric mice (hRN/hANG-Tg), whereas wild-type mice (C57BL/6J) showed little increase in BP. Cardiovascular remodeling with enhanced oxidative stress in hRN/hANG-Tg was markedly accelerated by NO inhibition compared with that in wild-type mice. Moreover, ACE2 mRNA expression and activity in cardiac tissue were markedly reduced in L-NAME-treated hRN/hANG-Tg. Co-administration of an angiotensin II type 1 (AT(1)) receptor blocker (ARB), olmesartan, inhibited L-NAME-induced cardiovascular remodeling and improved the reduction in cardiac ACE2. The preventive effect of olmesartan on cardiac hypertrophy was blunted by co-administration of a selective Ang-(1-7) antagonist, [D-Ala(7)]-Ang-(1-7). Conclusion Our findings demonstrate that cardiovascular remodeling induced by persistent NO inhibition was enhanced in hRN/hANG-Tg. An ARB, olmesartan, blunted cardiac remodeling induced by NO inhibition with RAS activation partially through the ACE2/Ang-(1-7)/Mas axis in addition to directly through its classical ACE/Ang II/AT(1) receptor axis-blocking action. J Hypertens 29: 2236-2245 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.