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

Angiotensin II receptors play an essential role in cardiovascular physiology and disease. The significance of angiotensin type II (AT ₂ ) receptors in cardiac disease still remains elusive. Thus, we tested in gene-targeted mice whether AT ₂ 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 AT ₂ 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 AT ₂ -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 AT ₂ receptors, and inhibition of NO production by N ^G -nitro- l -arginine methyl ester abolished the antihypertrophic effect of AT ₂ on cardiac myocytes. Our results demonstrate in a genetic mouse model that angiotensin II AT ₂ receptors exert an antihypertrophic effect in cardiac remodeling after myocardial cryoinjury and link the expression of cardiac eNOS to AT ₂ receptor activation.