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Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

Publication ,  Journal Article
Iaccarino, G; Smithwick, LA; Lefkowitz, RJ; Koch, WJ
Published in: Proc Natl Acad Sci U S A
March 30, 1999

Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

March 30, 1999

Volume

96

Issue

7

Start / End Page

3945 / 3950

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Recombinant Fusion Proteins
  • Rats
  • Muscle, Smooth, Vascular
  • Macromolecular Substances
  • Kinetics
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Genetic Therapy
 

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Iaccarino, G., Smithwick, L. A., Lefkowitz, R. J., & Koch, W. J. (1999). Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. Proc Natl Acad Sci U S A, 96(7), 3945–3950. https://doi.org/10.1073/pnas.96.7.3945
Iaccarino, G., L. A. Smithwick, R. J. Lefkowitz, and W. J. Koch. “Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.Proc Natl Acad Sci U S A 96, no. 7 (March 30, 1999): 3945–50. https://doi.org/10.1073/pnas.96.7.3945.
Iaccarino G, Smithwick LA, Lefkowitz RJ, Koch WJ. Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3945–50.
Iaccarino, G., et al. “Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.Proc Natl Acad Sci U S A, vol. 96, no. 7, Mar. 1999, pp. 3945–50. Pubmed, doi:10.1073/pnas.96.7.3945.
Iaccarino G, Smithwick LA, Lefkowitz RJ, Koch WJ. Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3945–3950.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

March 30, 1999

Volume

96

Issue

7

Start / End Page

3945 / 3950

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Recombinant Fusion Proteins
  • Rats
  • Muscle, Smooth, Vascular
  • Macromolecular Substances
  • Kinetics
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Genetic Therapy