Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice

J Clin Invest. 2005 Nov;115(11):3045-56. doi: 10.1172/JCI25330.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Bradycardia / genetics*
  • Bradycardia / metabolism
  • Bradycardia / pathology
  • Cells, Cultured
  • Electrocardiography
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / deficiency
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / deficiency
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Hypertrophy, Left Ventricular / genetics*
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / pathology
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Phenotype
  • Protein Kinase C-epsilon / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Angiotensin, Type 1 / deficiency*
  • Receptor, Angiotensin, Type 1 / genetics*
  • Receptor, Angiotensin, Type 1 / metabolism


  • Receptor, Angiotensin, Type 1
  • Protein Kinase C-epsilon
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gq-G11