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dc.contributor.author Kim, J
dc.contributor.author Zhang, L
dc.contributor.author Peppel, K
dc.contributor.author Wu, JH
dc.contributor.author Zidar, DA
dc.contributor.author Brian, L
dc.contributor.author DeWire, SM
dc.contributor.author Exum, ST
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Freedman, NJ
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T21:20:08Z
dc.date.issued 2008-07-03
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/18519945
dc.identifier CIRCRESAHA.108.172338
dc.identifier.citation Circ Res, 2008, 103 (1), pp. 70 - 79
dc.identifier.uri http://hdl.handle.net/10161/5911
dc.description.abstract 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.
dc.format.extent 70 - 79
dc.language eng
dc.relation.ispartof Circ Res
dc.relation.isversionof 10.1161/CIRCRESAHA.108.172338
dc.subject Animals
dc.subject Aorta
dc.subject Arrestins
dc.subject Atherosclerosis
dc.subject Cell Movement
dc.subject Cell Proliferation
dc.subject Extracellular Signal-Regulated MAP Kinases
dc.subject Graft Occlusion, Vascular
dc.subject Hyperplasia
dc.subject MAP Kinase Signaling System
dc.subject Mice
dc.subject Mice, Knockout
dc.subject Myocytes, Smooth Muscle
dc.subject Receptors, LDL
dc.title Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.
dc.type Journal Article
duke.description.endpage 79 en_US
duke.description.issue 1 en_US
duke.description.startpage 70 en_US
duke.description.volume 103 en_US
dc.relation.journal Circulation Research en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/18519945
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 103
dc.identifier.eissn 1524-4571

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