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Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.
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.
Type
Journal articleSubject
AnimalsAorta
Arrestins
Atherosclerosis
Cell Movement
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases
Graft Occlusion, Vascular
Hyperplasia
MAP Kinase Signaling System
Mice
Mice, Knockout
Myocytes, Smooth Muscle
Receptors, LDL
beta-Arrestins
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https://hdl.handle.net/10161/5911Published Version (Please cite this version)
10.1161/CIRCRESAHA.108.172338Publication Info
Kim, Jihee; Zhang, Lisheng; Peppel, Karsten; Wu, Jiao-Hui; Zidar, David A; Brian,
Leigh; ... Freedman, Neil J (2008). Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling
smooth muscle cell proliferation and migration. Circ Res, 103(1). pp. 70-79. 10.1161/CIRCRESAHA.108.172338. Retrieved from https://hdl.handle.net/10161/5911.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Neil Jonathan Freedman
Professor of Medicine
Our work focuses on atherosclerosis-related signal transduction and the genetic bases
of atherosclerosis and vein graft failure, both in vitro and in vivo. We investigate
the regulation of receptor protein tyrosine kinases by G protein-coupled receptor
kinases (GRKs), and the role of GRKs and β-arrestins in atherosclerosis; the
role of tumor necrosis factor and its receptors in atherosclerosis; and the role of
the dual Rho-GEF kalirin in atherosclerosis. For in vivo modeling of atherosclero
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
Lisheng Zhang
Assistant Professor in Medicine
My research efforts involves studying the pathogenesis of vein graft neointimal hyperplasia
and atherosclerosis. The greatest amount of my time in the past years has been devoted
to developing and characterizing our interposition vein graft model in mice. This
model allows us to use IVC to carotid artery transplants between congenic mice. These
transplants allow us to ask the questions about which gene products contribute to
the pathogenesis of vein graft disease. In addition, I hav
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