Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice.

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 NG-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.