The Angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor - Mediated hypertrophy

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.