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(Hypertension. 2005;46:1347.)
© 2005 American Heart Association, Inc.

Original Articles

The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

Angelo D’Amore; M. Jane Black; Walter G. Thomas

From the Department of Anatomy and Cell Biology (A.D., M.J.B.), Monash University, Clayton, Victoria, Australia; and Molecular Endocrinology Laboratory (A.D., W.G.T.), Baker Heart Research Institute, Prahran, Victoria, Australia.

Correspondence to Dr Walter Thomas, Baker Heart Research Institute, PO Box 6492, St. Kilda Rd Central, Melbourne, 8008, Australia. E-mail walter.thomas{at}baker.edu.au

Angiotensin II (Ang II) has important actions on the heart via type 1 (AT₁) and type 2 (AT₂) receptors. The link between AT₁ receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT₂ receptor, which reportedly antagonizes the AT₁ receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT₂ receptor and its modulation of the AT₁ receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT₁ and AT₂ to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT₁/AT₂ stoichiometry on cardiomyocyte hypertrophy. In myocytes expressing only the AT₁ receptor, Ang II stimulation promoted robust hypertrophy (increased protein:DNA ratio and phenotypic changes) via activation of mitogen-activated protein kinases (MAPKs). Titration of the AT₂ receptor against the AT₁ receptor did not inhibit Ang II–mediated cardiomyocyte hypertrophy. Instead, basal and Ang II–mediated hypertrophy was increased in line with the amplified expression of the AT₂ receptor, indicating a capacity for the AT₂ receptor to enhance basal cardiomyocyte growth. Indeed, expression of the AT₂ receptor alone resulted in hypertrophy; remarkably, this was unaffected by Ang II stimulation or the AT₂ receptor–specific ligands PD123319 and CGP42112. Although previous studies have indicated that the AT₂ receptor can antagonize MAPK activation via the AT₁ receptor, we found no evidence for this in cardiomyocytes. Thus, the AT₂ receptor promotes ligand-independent, constitutive cardiomyocyte hypertrophy and does not directly antagonize the AT₁ receptor in this setting.

Key Words: angiotensin II • hypertrophy • myocytes • rats • receptors

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