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Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.

Publication ,  Journal Article
Kim, J; Zhang, L; Peppel, K; Wu, J-H; Zidar, DA; Brian, L; DeWire, SM; Exum, ST; Lefkowitz, RJ; Freedman, NJ
Published in: Circ Res
July 3, 2008

Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins beta-arrestin1 and -2 might regulate this pathological process. Deficiency of beta-arrestin2 in ldlr(-/-) mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that beta-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, beta-arrestin1(-/-), and beta-arrestin2(-/-) mice. Neointimal hyperplasia was enhanced in beta-arrestin1(-/-) mice, and diminished in beta-arrestin2(-/-) mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in beta-arrestin2(-/-) mice was not altered by transplantation with either wild-type or beta-arrestin2(-/-) bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in beta-arrestin1(-/-) and decreased in beta-arrestin2(-/-) mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in beta-arrestin1(-/-) SMCs and less in beta-arrestin2(-/-) SMCs. Proliferation was less than wild type in beta-arrestin2(-/-) SMCs but not in beta-arrestin2(-/-) endothelial cells. We conclude that beta-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by beta-arrestin2 and beta-arrestin1. These findings identify inhibition of beta-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.

Duke Scholars

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

July 3, 2008

Volume

103

Issue

1

Start / End Page

70 / 79

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Receptors, LDL
  • Myocytes, Smooth Muscle
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Extracellular Signal-Regulated MAP Kinases
  • Cell Proliferation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kim, J., Zhang, L., Peppel, K., Wu, J.-H., Zidar, D. A., Brian, L., … Freedman, N. J. (2008). Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ Res, 103(1), 70–79. https://doi.org/10.1161/CIRCRESAHA.108.172338
Kim, Jihee, Lisheng Zhang, Karsten Peppel, Jiao-Hui Wu, David A. Zidar, Leigh Brian, Scott M. DeWire, Sabrina T. Exum, Robert J. Lefkowitz, and Neil J. Freedman. “Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.Circ Res 103, no. 1 (July 3, 2008): 70–79. https://doi.org/10.1161/CIRCRESAHA.108.172338.
Kim J, Zhang L, Peppel K, Wu J-H, Zidar DA, Brian L, et al. Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ Res. 2008 Jul 3;103(1):70–9.
Kim, Jihee, et al. “Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.Circ Res, vol. 103, no. 1, July 2008, pp. 70–79. Pubmed, doi:10.1161/CIRCRESAHA.108.172338.
Kim J, Zhang L, Peppel K, Wu J-H, Zidar DA, Brian L, DeWire SM, Exum ST, Lefkowitz RJ, Freedman NJ. Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ Res. 2008 Jul 3;103(1):70–79.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

July 3, 2008

Volume

103

Issue

1

Start / End Page

70 / 79

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Receptors, LDL
  • Myocytes, Smooth Muscle
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Extracellular Signal-Regulated MAP Kinases
  • Cell Proliferation