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Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure.

Publication ,  Journal Article
Eckhart, AD; Ozaki, T; Tevaearai, H; Rockman, HA; Koch, WJ
Published in: Mol Pharmacol
April 2002

Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). beta-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences systemic vascular resistance. GPCR kinases (GRKs), including GRK2 (or betaARK1), phosphorylate and desensitize agonist-activated betaARs. Myocardial GRK2 levels are increased in heart failure and data suggest that vascular levels may also be elevated in hypertension. Therefore, we generated transgenic mice with vascular smooth muscle (VSM) targeted overexpression of GRK2, using a portion of the SM22alpha promoter, to determine its impact on vascular betaAR regulation. VSM betaAR signaling, as determined by adenylyl cyclase and mitogen-activated protein (MAP) kinase activation assays, was attenuated when GRK2 was overexpressed 2- to 3-fold. In vivo vasodilation in response to betaAR stimulation using isoproterenol was attenuated and conscious resting mean arterial blood pressure was elevated from 96 +/- 2 mm Hg in nontransgenic littermate control (NLC) mice (n = 9) to 112 +/- 3 mm Hg and 117 +/- 2 mm Hg in two different lines of SM22alpha-GRK2 transgenic mice (n = 7 and n = 5, respectively; p < 0.05). Interestingly, medial VSM thickness was increased 30% from 29.8 +/- 1.6 microm in NLC mice (n = 6) to 39.4 +/- 1.6 microm in SM22alpha-GRK2 mice (n = 7) (p < 0.05) and vascular GRK2 overexpression was sufficient to cause cardiac hypertrophy. These data indicate that we have developed a unique mouse model of hypertension, providing insight into the contribution that vascular betaAR signaling makes toward resting blood pressure and overall cardiovascular regulation. Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension.

Duke Scholars

Published In

Mol Pharmacol

DOI

ISSN

0026-895X

Publication Date

April 2002

Volume

61

Issue

4

Start / End Page

749 / 758

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Rest
  • Receptors, Adrenergic, beta
  • Pharmacology & Pharmacy
  • Muscle, Smooth, Vascular
  • Mice, Transgenic
  • Mice
  • Hypertension
  • G-Protein-Coupled Receptor Kinase 3
 

Citation

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Eckhart, A. D., Ozaki, T., Tevaearai, H., Rockman, H. A., & Koch, W. J. (2002). Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure. Mol Pharmacol, 61(4), 749–758. https://doi.org/10.1124/mol.61.4.749
Eckhart, Andrea D., Tohru Ozaki, Hendrik Tevaearai, Howard A. Rockman, and Walter J. Koch. “Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure.Mol Pharmacol 61, no. 4 (April 2002): 749–58. https://doi.org/10.1124/mol.61.4.749.
Eckhart, Andrea D., et al. “Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure.Mol Pharmacol, vol. 61, no. 4, Apr. 2002, pp. 749–58. Pubmed, doi:10.1124/mol.61.4.749.

Published In

Mol Pharmacol

DOI

ISSN

0026-895X

Publication Date

April 2002

Volume

61

Issue

4

Start / End Page

749 / 758

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Rest
  • Receptors, Adrenergic, beta
  • Pharmacology & Pharmacy
  • Muscle, Smooth, Vascular
  • Mice, Transgenic
  • Mice
  • Hypertension
  • G-Protein-Coupled Receptor Kinase 3