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Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors.

Publication ,  Journal Article
Peppel, K; Jacobson, A; Huang, X; Murray, JP; Oppermann, M; Freedman, NJ
Published in: Circulation
August 15, 2000

BACKGROUND: Neointimal hyperplasia involves activation of smooth muscle cells (SMCs) by several G protein-coupled receptor (GPCR) agonists, including endothelin-1, angiotensin II, thrombin, and thromboxane A(2). Signaling of many GPCRs is diminished by GPCR kinase-2 (GRK2). We therefore tested whether overexpression of GRK2 in SMCs could diminish mitogenic signaling elicited by agonists implicated in the pathogenesis of neointimal hyperplasia. METHODS AND RESULTS: Overexpression of GRK2 was achieved in primary rabbit aortic SMCs with a recombinant adenovirus. Control SMCs were infected with an empty vector adenovirus. Inositol phosphate responses to endothelin-1, angiotensin II, thrombin agonist peptide, and platelet-derived growth factor (PDGF) were attenuated by 37% to 72% in GRK2-overexpressing cells (P<0.01), but the response to the thromboxane A(2) analogue U46619 was unaffected. GRK2 also inhibited SMC [(3)H]thymidine incorporation stimulated not only by these agonists (by 30% to 60%, P<0.01) but also by 10% FBS (by 35%, P<0. 05). However, GRK2 overexpression had no effect on epidermal growth factor-induced [(3)H]thymidine incorporation. Agonist-induced tyrosine phosphorylation of the PDGF-beta receptor, but not the epidermal growth factor receptor, was reduced in GRK2-overexpressing SMCs. GRK2 overexpression also reduced SMC proliferation in response to endothelin-1, PDGF, and 10% FBS by 62%, 51%, and 29%, respectively (P<0.01), without any effect on SMC apoptosis. CONCLUSIONS: GRK2 overexpression diminishes SMC mitogenic signaling and proliferation stimulated by PDGF or agonists for several GPCRs. Gene transfer of GRK2 may therefore be therapeutically useful for neointimal hyperplasia.

Duke Scholars

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

August 15, 2000

Volume

102

Issue

7

Start / End Page

793 / 799

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Thymidine
  • Signal Transduction
  • Receptors, Platelet-Derived Growth Factor
  • Rabbits
  • Phosphatidylinositols
  • Muscle, Smooth, Vascular
  • Mitogens
  • Male
  • Hydrolysis
 

Citation

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Peppel, K., Jacobson, A., Huang, X., Murray, J. P., Oppermann, M., & Freedman, N. J. (2000). Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors. Circulation, 102(7), 793–799. https://doi.org/10.1161/01.cir.102.7.793
Peppel, K., A. Jacobson, X. Huang, J. P. Murray, M. Oppermann, and N. J. Freedman. “Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors.Circulation 102, no. 7 (August 15, 2000): 793–99. https://doi.org/10.1161/01.cir.102.7.793.
Peppel, K., et al. “Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors.Circulation, vol. 102, no. 7, Aug. 2000, pp. 793–99. Pubmed, doi:10.1161/01.cir.102.7.793.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

August 15, 2000

Volume

102

Issue

7

Start / End Page

793 / 799

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Thymidine
  • Signal Transduction
  • Receptors, Platelet-Derived Growth Factor
  • Rabbits
  • Phosphatidylinositols
  • Muscle, Smooth, Vascular
  • Mitogens
  • Male
  • Hydrolysis