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

Abstract

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