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 (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 ...