Published Online
on October 27, 2003

A more recent version of this article appeared on December 1, 2003

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Submitted on August 20, 2003
Revised on September 9, 2003

Cardiac Hypertrophy Is Associated With Decreased eNOS Expression in Angiotensin AT₂ Receptor-Deficient Mice

Marc Brede; Wilhelm Roell; Oliver Ritter; Frank Wiesmann; Roland Jahns; Axel Haase; Bernd K. Fleischmann; and Lutz Hein^*

From the Institut für Pharmakologie und Toxikologie (M.B., R.J., L.H.), Medizinische Klinik (O.R., F.W.), Medizinische Poliklinik (R.J.), and Physikalisches Institut (F.W., A.H.), Universität Würzburg, Würzburg; the Klinik und Poliklinik für Herzchirurgie (W.R.), Universität Bonn, Bonn; and Institut für Neurophysiologie (B.K.F.), Universität Köln, Köln, Germany.

^* To whom correspondence should be addressed. E-mail: hein{at}toxi.uni-wuerzburg.de.

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.

Key words: myocardial infarction • cryoinjury • animals, transgenic • mice • nitric oxide synthase

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