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

Kim, Jihee

Zhang, Lisheng

Peppel, Karsten

Wu, Jiao-Hui

Zidar, David A

Brian, Leigh

DeWire, Scott M

Exum, Sabrina T

Lefkowitz, Robert J

Freedman, Neil J

United States

2012-10-22T21:20:08Z

2008-07-03

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.

https://www.ncbi.nlm.nih.gov/pubmed/18519945

CIRCRESAHA.108.172338

1524-4571

https://hdl.handle.net/10161/5911

eng

Ovid Technologies (Wolters Kluwer Health)

Circ Res

10.1161/CIRCRESAHA.108.172338

Circulation Research

Animals

Aorta

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

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

Journal article

Lefkowitz, Robert J|0000-0003-1472-7545

Freedman, Neil J|0000-0002-8593-8676

1

103

https://www.ncbi.nlm.nih.gov/pubmed/18519945

70

79

1

Basic Science Departments

Biochemistry

Cell Biology

Chemistry

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Cardiology

Pathology

School of Medicine

Trinity College of Arts & Sciences

Published

103