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

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