on May 10, 2007
Published online before print May 10, 2007, doi: 10.1161/ATVBAHA.107.145086
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Submitted on November 21, 2006
Accepted on April 11, 2007
Elevated Cholesterol Levels in the Plasma Membranes of Macrophages Inhibit Migration by Disrupting RhoA Regulation
Tomokazu Nagao ;
From the Departments of Biochemistry (T.N., C.Q., I.G., F.R.M.) and Surgery (L.M.P.), Weill Medical College of Cornell University, New York.
* To whom correspondence should be addressed. E-mail: LPierini{at}med.cornell.edu.
Objective--Atherogenesis begins as small subendothelial accumulations of foam cells that develop through unregulated uptake of modified and aggregated low-density lipoprotein (LDL). The reason why foam cells remain in the atherosclerotic plaque rather than migrating out of the area is unclear. We tested the hypothesis that elevated membrane cholesterol levels, which may result from interactions with aggregated LDL, affect macrophage migration.
Methods and Results--Cholesterol loading by incubation with cholesterol-chelated methyl-
-cyclodextrin decreased migration of J774A.1 macrophages toward complement 5a (C5a) in transwell migration assays, even though cholesterol-loaded macrophages responded to a bath application of C5a. In a micropipette polarization assay, cholesterol-loaded cells polarized toward a C5a gradient. In a transwell migration assay, cholesterol-loaded cells extended lamellae through the filter pores but were unable to translocate their cell bodies. Cholesterol loading decreased both the cellular levels of GTP-bound active RhoA and the phosphorylation of myosin light chain. Expression of constitutively active RhoA largely prevented the inhibition of cell migration by cholesterol loading.
Conclusions--These results suggest that increases in plasma membrane cholesterol content alter RhoA activation, resulting in inhibition of cell migration. These findings provide one possible explanation for the retention of foam cells in atherosclerotic lesions.
Key words: foam cells • atherosclerosis • actin • motility • cyclodextrin
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