on October 28, 2004
Published online before print October 28, 2004, doi: 10.1161/01.ATV.0000149145.00865.d9
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Submitted on August 4, 2004
Accepted on October 14, 2004
Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner
Zhenze Zhao ;
From the Department of Internal Medicine and Graduate Center for Nutritional Sciences (Z.Z., M.C.d.B., L.C., R.A., F.C.d.B., W.J.S.d.V., D.R.v.d.W.), University of Kentucky Medical Center, Lexington; and Department of Veterans Affairs Medical Center (Z.Z., M.C.d.B., L.C., F.C.d.B., W.J.S.d.V., D.R.v.d.W.), Lexington, Ky.
* To whom correspondence should be addressed. E-mail: dvwest1{at}uky.edu.
Objective--To investigate the potential of circulating low-density lipoprotein (LDL), isolated from apolipoprotein E (apoE)-deficient mice (E-/-LDL) and from LDL receptor-deficient mice (Lr-/-LDL), to induce foam cell formation.
Methods and Results--Binding studies using COS-7 cells overexpressing CD36, J774 cells, and mouse peritoneal macrophages (MPMs) unexpectedly showed for the first time that E-/-LDL, which is enriched in cholesterol, is a high-affinity ligand for CD36 and exhibited greater macrophage uptake than Lr-/-LDL or normal LDL. Minimal copper-mediated oxidization of Lr-/-LDL or C57LDL in vitro resulted in increased ligand internalization, although cell uptake of these oxidized LDLs was lower than that of E-/-LDL, even at oxidation levels similar to that found in E-/-LDL. Treatment of MPMs with E-/-LDL and Lr-/-LDL (to a 2- to 3-fold lesser extent), but not normal LDL, resulted in significant cellular cholesteryl ester accumulation and foam cell formation. Experiments using MPMs lacking CD36, scavenger receptor class A (SR-A), or both, indicated a major contribution of CD36 (
50%), and to a lesser extent, SR-A (24% to 30%), to E-/-LDL uptake.
Conclusions--Because of its increased state of oxidation and high cholesterol content, LDL in apoE-deficient mice acts in a proatherogenic manner, without requiring further modification in the vascular wall, to induce foam cell formation through its uptake by scavenger receptors.
Key words: apolipoprotein E • macrophages • scavenger receptor • CD36 • SR-A
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