Cardiac Hypertrophy Is Associated With Decreased eNOS Expression in Angiotensin AT 2 Receptor–Deficient Mice

Abstract

Angiotensin II receptors play an essential role in cardiovascular physiology and disease. The significance of angiotensin type II (AT₂) receptors in cardiac disease still remains elusive. Thus, we tested in gene-targeted mice whether AT₂ receptors modulate cardiac function and remodeling after experimental myocardial injury. To generate myocardial infarcts of reproducible size, a cryolesion was generated at the free wall of the left ventricle of wild-type mice (Agtr2+/Y) and mice carrying a deletion of the AT₂ receptor gene (Agtr2-/Y). Postinjury remodeling was followed up for 4 weeks after cryoinjury. The cryoprocedure led to an increased heart weight/body weight ratio and heart weight/tibia length ratio in AT₂-deficient mice compared with control mice. Morphometric analysis revealed a significant increase in myocyte cross-sectional area after cardiac injury (infarct vs sham Agtr2+/Y, +53%; vs Agtr2-/Y, +95%). Expression of endothelial nitric oxide synthase (eNOS) was significantly lower in hearts from Agtr2-/Y than from Agtr2+/Y mice. eNOS downregulation was accompanied by a decrease in cardiac cGMP levels in Agtr2-/Y mice. In isolated murine cardiomyocytes, angiotensin II induced eNOS expression through AT₂ receptors, and inhibition of NO production by N^G-nitro-l-arginine methyl ester abolished the antihypertrophic effect of AT₂ on cardiac myocytes. Our results demonstrate in a genetic mouse model that angiotensin II AT₂ receptors exert an antihypertrophic effect in cardiac remodeling after myocardial cryoinjury and link the expression of cardiac eNOS to AT₂ receptor activation.