Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor

Angiotensin II (Ang II) may cause cardiac hypertrophy via type 1 Ang II receptors (AT1) on cardiomyocytes and through growth factors released from cardiac fibroblasts. Whereas cardiomyocyte-specific AT1 receptor expression produces cardiac hypertrophy and remodeling in vivo, delineation of the signals that mediate growth to Ang II is challenging because the prevailing in vitro model (cultured neonatal cardiomyocytes) expresses low levels of AT1 receptor and responds inconsistently to Ang II. In this study, when AT1A receptors were expressed using adenovirus in cultured neonatal cardiomyocytes, Ang II stimulated a robust hypertrophy that was not secondary to the release of cardiac fibroblast-derived factors, specifically endothelin-1. Hypertrophy was accompanied by the induction of the immediate-early response genes, c-fos and c-jun, and reexpression of atrial natriuretic peptide (ANP). Ang II–induced activation of an ANP promoter-reporter was inhibited by the dominant/negative mutants, G&agr;qI and N17Ras, indicating that hypertrophic signaling by the AT1A receptor is via heterotrimeric G protein coupling and downstream Ras pathways. AT1A-mediated cardiomyocyte hypertrophy and mitogen-activated protein kinase (MAPK) activation were inhibited by the MAPK kinase inhibitor, PD98059, and the epidermal growth factor (EGF) receptor kinase antagonist, AG1478, but not by PKC inhibitor, bisindolylmaleimide-1. Moreover, Ang II–induced MAPK activation was prevented by treatment with a matrix metalloproteinase inhibitor, consistent with the tyrosine phosphorylation of the EGF receptor in response to AT1A receptor activation. These data unequivocally demonstrate that Ang II can directly promote cardiac myocyte growth via AT1A receptors expressed on these cells and reveal for the first time the important contribution of EGF receptor–transactivated MAPK signaling to this process.

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