Published online before print June 2, 2008, doi: 10.1161/CIRCRESAHA.108.172338
© 2008 American Heart Association, Inc.
Cellular Biology |
β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration
From the Departments of Medicine (Cardiology) (J.K., L.Z., K.P., J.-H.W., D.A.Z., L.B., S.M.D., S.T.E., R.J.L., N.J.F.), Biochemistry (R.J.L.), Cell Biology (N.J.F.), and the Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC. Present address for K.P.: Jefferson University Center for Translational Medicine, Philadelphia, Pa.
Correspondence to Neil J. Freedman, Box 3187 or 3821, Duke University Medical Center, Durham, NC 27710. E-mail neil.freedman{at}duke.edu
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 β-arrestin1 and -2 might regulate this pathological process. Deficiency of β-arrestin2 in ldlr–/– mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that β-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, β-arrestin1–/–, and β-arrestin2–/– mice. Neointimal hyperplasia was enhanced in β-arrestin1–/– mice, and diminished in β-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 β-arrestin2–/– mice was not altered by transplantation with either wild-type or β-arrestin2–/– bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in β-arrestin1–/– and decreased in β-arrestin2–/– mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in β-arrestin1–/– SMCs and less in β-arrestin2–/– SMCs. Proliferation was less than wild type in β-arrestin2–/– SMCs but not in β-arrestin2–/– endothelial cells. We conclude that β-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by β-arrestin2 and β-arrestin1. These findings identify inhibition of β-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.
Key Words: arteriosclerosis • muscle • smooth • signal transduction • receptors • endothelium
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