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

Publisher Website
Google Scholar
Abstract
Angiotensin II (Ang II) has important actions on the heart via type 1 (AT1) and type 2 (AT2) receptors. The link between AT1receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT2receptor, which reportedly antagonizes the AT1receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT2receptor and its modulation of the AT1receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT1and AT2to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT1/AT2stoichiometry on cardiomyocyte hypertrophy. In myocytes expressing only the AT1receptor, Ang II stimulation promoted robust hypertrophy (increased protein:DNA ratio and phenotypic changes) via activation of mitogen-activated protein kinases (MAPKs). Titration of the AT2receptor against the AT1receptor 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 AT2receptor, indicating a capacity for the AT2receptor to enhance basal cardiomyocyte growth. Indeed, expression of the AT2receptor alone resulted in hypertrophy; remarkably, this was unaffected by Ang II stimulation or the AT2receptor–specific ligands PD123319 and CGP42112. Although previous studies have indicated that the AT2receptor can antagonize MAPK activation via the AT1receptor, we found no evidence for this in cardiomyocytes. Thus, the AT2receptor promotes ligand-independent, constitutive cardiomyocyte hypertrophy and does not directly antagonize the AT1receptor in this setting.