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.
β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration
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Medientyp:
E-Artikel
Titel:
β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration
Beteiligte:
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.
Beschreibung:
<jats:p>
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
<jats:italic>ldlr</jats:italic>
<jats:sup>−/−</jats:sup>
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
<jats:sup>−/−</jats:sup>
, and β-arrestin2
<jats:sup>−/−</jats:sup>
mice. Neointimal hyperplasia was enhanced in β-arrestin1
<jats:sup>−/−</jats:sup>
mice, and diminished in β-arrestin2
<jats:sup>−/−</jats:sup>
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
<jats:sup>−/−</jats:sup>
mice was not altered by transplantation with either wild-type or β-arrestin2
<jats:sup>−/−</jats:sup>
bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in β-arrestin1
<jats:sup>−/−</jats:sup>
and decreased in β-arrestin2
<jats:sup>−/−</jats:sup>
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
<jats:sup>−/−</jats:sup>
SMCs and less in β-arrestin2
<jats:sup>−/−</jats:sup>
SMCs. Proliferation was less than wild type in β-arrestin2
<jats:sup>−/−</jats:sup>
SMCs but not in β-arrestin2
<jats:sup>−/−</jats:sup>
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.
</jats:p>