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Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.

Publication ,  Journal Article
Wu, J-H; Fanaroff, AC; Sharma, KC; Smith, LS; Brian, L; Eipper, BA; Mains, RE; Freedman, NJ; Zhang, L
Published in: Arterioscler Thromb Vasc Biol
April 2013

OBJECTIVE: Kalirin is a multifunctional protein that contains 2 guanine nucleotide exchange factor domains for the GTPases Rac1 and RhoA. Variants of KALRN have been associated with atherosclerosis in humans, but Kalirin's activity has been characterized almost exclusively in the central nervous system. We therefore tested the hypothesis that Kalirin functions as a Rho-guanine nucleotide exchange factor in arterial smooth muscle cells (SMCs). APPROACH AND RESULTS: Kalirin-9 protein is expressed abundantly in aorta and bone marrow, as well as in cultured SMCs, endothelial cells, and macrophages. Moreover, arterial Kalirin was upregulated during early atherogenesis in apolipoprotein E-deficient mice. In cultured SMCs, signaling was affected similarly in 3 models of Kalirin loss-of-function: heterozygous Kalrn deletion, Kalirin RNAi, and treatment with the Kalirin Rho-guanine nucleotide exchange factor -1 inhibitor 1-(3-nitrophenyl)-1H-pyrrole-2,5-dione. With reduced Kalirin function, SMCs showed normal RhoA activation but diminished Rac1 activation, assessed as reduced Rac-GTP levels, p21-activated kinase autophosphorylation, and SMC migration. Kalrn(-/+) SMCs proliferated 30% less rapidly than wild-type SMCs. Neointimal hyperplasia engendered by carotid endothelial denudation was ≈60% less in Kalrn(-/+) and SMC-specific Kalrn(-/+) mice than in control mice. CONCLUSIONS: Kalirin functions as a guanine nucleotide exchange factor for Rac1 in SMCs, and promotes SMC migration and proliferation both in vitro and in vivo.

Duke Scholars

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

April 2013

Volume

33

Issue

4

Start / End Page

702 / 708

Location

United States

Related Subject Headings

  • rhoA GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rac GTP-Binding Proteins
  • p21-Activated Kinases
  • Transfection
  • Signal Transduction
  • RNA Interference
  • Protein Kinase Inhibitors
  • Phosphorylation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wu, J.-H., Fanaroff, A. C., Sharma, K. C., Smith, L. S., Brian, L., Eipper, B. A., … Zhang, L. (2013). Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells. Arterioscler Thromb Vasc Biol, 33(4), 702–708. https://doi.org/10.1161/ATVBAHA.112.300234
Wu, Jiao-Hui, Alexander C. Fanaroff, Krishn C. Sharma, Liisa S. Smith, Leigh Brian, Betty A. Eipper, Richard E. Mains, Neil J. Freedman, and Lisheng Zhang. “Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.Arterioscler Thromb Vasc Biol 33, no. 4 (April 2013): 702–8. https://doi.org/10.1161/ATVBAHA.112.300234.
Wu J-H, Fanaroff AC, Sharma KC, Smith LS, Brian L, Eipper BA, et al. Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells. Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):702–8.
Wu, Jiao-Hui, et al. “Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.Arterioscler Thromb Vasc Biol, vol. 33, no. 4, Apr. 2013, pp. 702–08. Pubmed, doi:10.1161/ATVBAHA.112.300234.
Wu J-H, Fanaroff AC, Sharma KC, Smith LS, Brian L, Eipper BA, Mains RE, Freedman NJ, Zhang L. Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells. Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):702–708.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

April 2013

Volume

33

Issue

4

Start / End Page

702 / 708

Location

United States

Related Subject Headings

  • rhoA GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rac GTP-Binding Proteins
  • p21-Activated Kinases
  • Transfection
  • Signal Transduction
  • RNA Interference
  • Protein Kinase Inhibitors
  • Phosphorylation