title: An angiotensin II type 1 receptor mutant lacking epidermal growth factor receptor transactivation does not induce angiotensin II-mediated cardiac hypertrophy.
abstract: We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT(1)Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein-coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT(1)R (Tg-WT) and an AT(1)R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of Galphaq/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice. In conclusion, overexpression of AT(1)-Y319F in cardiac myocytes diminished EGFR transactivation and inhibited a pathological form of cardiac hypertrophy. The YIPP motif in the AT(1)R plays an important role in mediating cardiac hypertrophy in vivo.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Jonathan
authors.initials: J
authors.lastname: Galeotti
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Eric
authors.initials: E
authors.lastname: Holle
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Yu
authors.forename: Thomas
authors.initials: T
authors.lastname: Wagner
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000804:Angiotensin II; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000139:chemically induced* / Q000235:genetics*; D003971:Diastole; D004452:Echocardiography; D066246:ErbB Receptors / Q000235:genetics*; D005355:Fibrosis; D005799:Genes, Dominant; D006321:Heart / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D010649:Phenylalanine; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D015533:Transcriptional Activation; D014443:Tyrosine; D016277:Ventricular Function, Left
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D014443:Tyrosine; D010649:Phenylalanine; D066246:ErbB Receptors