title: Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice.
abstract: Ang II type 1 (AT1) receptors activate both conventional heterotrimeric G protein-dependent and unconventional G protein-independent mechanisms. We investigated how these different mechanisms activated by AT1 receptors affect growth and death of cardiac myocytes in vivo. Transgenic mice with cardiac-specific overexpression of WT AT1 receptor (AT1-WT; Tg-WT mice) or an AT1 receptor second intracellular loop mutant (AT1-i2m; Tg-i2m mice) selectively activating G(alpha)q/G(alpha)i-independent mechanisms were studied. Tg-i2m mice developed more severe cardiac hypertrophy and bradycardia coupled with lower cardiac function than Tg-WT mice. In contrast, Tg-WT mice exhibited more severe fibrosis and apoptosis than Tg-i2m mice. Chronic Ang II infusion induced greater cardiac hypertrophy in Tg-i2m compared with Tg-WT mice whereas acute Ang II administration caused an increase in heart rate in Tg-WT but not in Tg-i2m mice. Membrane translocation of PKCepsilon, cytoplasmic translocation of G(alpha)q, and nuclear localization of phospho-ERKs were observed only in Tg-WT mice while activation of Src and cytoplasmic accumulation of phospho-ERKs were greater in Tg-i2m mice, consistent with the notion that G(alpha)q/G(alpha)i-independent mechanisms are activated in Tg-i2m mice. Cultured myocytes expressing AT1-i2m exhibited a left and upward shift of the Ang II dose-response curve of hypertrophy compared with those expressing AT1-WT. Thus, the AT1 receptor mediates downstream signaling mechanisms through G(alpha)q/G(alpha)i-dependent and -independent mechanisms, which induce hypertrophy with a distinct phenotype.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Jonathan
authors.initials: J
authors.lastname: Galeotti
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Malthi
authors.initials: M
authors.lastname: Masurekar
authors.forename: Jill
authors.initials: J
authors.lastname: Thaisz
authors.forename: Keiichi
authors.initials: K
authors.lastname: Irie
authors.forename: Eric
authors.initials: E
authors.lastname: Holle
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Yu
authors.forename: Sabina
authors.initials: S
authors.lastname: Kupershmidt
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Thomas
authors.initials: T
authors.lastname: Wagner
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yatani
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001919:Bradycardia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004562:Electrocardiography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D044140:Receptor, Angiotensin, Type 1; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11