This Article Full Text Full Text (PDF) All Versions of this Article: 46/6/1347    most recent 01.HYP.0000193504.51489.cfv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by D’Amore, A. Articles by Thomas, W. G. Search for Related Content PubMed PubMed Citation Articles by D’Amore, A. Articles by Thomas, W. G. Related Collections ACE/Angiotension receptors Hypertrophy Related Article

(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

Related Article:

The Continuing Saga of the AT2 Receptor: A Case of the Good, the Bad, and the Innocuous

Timothy L. Reudelhuber
Hypertension 2005 46: 1261-1262. [Full Text] [PDF]

This article has been cited by other articles:

				L. Leatherbury, Q. Yu, B. Chatterjee, D. L. Walker, Z. Yu, X. Tian, and C. W. Lo A novel mouse model of X-linked cardiac hypertrophy Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2701 - H2711. [Abstract] [Full Text] [PDF]

				S. Eguchi Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor Circ. Res., May 23, 2008; 102(10): 1143 - 1145. [Full Text] [PDF]

				X. Yan, A. J. T. Schuldt, R. L. Price, I. Amende, F.-F. Liu, K. Okoshi, K. K. L. Ho, A. J. Pope, T. K. Borg, B. H. Lorell, et al. Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1274 - H1281. [Abstract] [Full Text] [PDF]

				M. Konigshoff, A. Wilhelm, A. Jahn, D. Sedding, O. V. Amarie, B. Eul, W. Seeger, L. Fink, A. Gunther, O. Eickelberg, et al. The Angiotensin II Receptor 2 Is Expressed and Mediates Angiotensin II Signaling in Lung Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2007; 37(6): 640 - 650. [Abstract] [Full Text] [PDF]

				M. Mogi, M. Iwai, and M. Horiuchi Emerging Concepts of Regulation of Angiotensin II Receptors: New Players and Targets for Traditional Receptors Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2532 - 2539. [Abstract] [Full Text] [PDF]

				P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]

				H. Suzuki, K. Eguchi, H. Ohtsu, S. Higuchi, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor Endocrinology, December 1, 2006; 147(12): 5914 - 5920. [Abstract] [Full Text] [PDF]

				J. Chen and J. L. Mehta Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1738 - H1745. [Abstract] [Full Text] [PDF]

				M. H. Strauss and A. S. Hall Angiotensin Receptor Blockers May Increase Risk of Myocardial Infarction: Unraveling the ARB-MI Paradox Circulation, August 22, 2006; 114(8): 838 - 854. [Full Text] [PDF]

				T. L. Reudelhuber The Continuing Saga of the AT2 Receptor: A Case of the Good, the Bad, and the Innocuous Hypertension, December 1, 2005; 46(6): 1261 - 1262. [Full Text] [PDF]