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 ( 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.