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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:168.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner

Zhenze Zhao; Maria C. de Beer; Lei Cai; Reto Asmis; Frederick C. de Beer; Willem J.S. de Villiers; Deneys R. van der Westhuyzen

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.

Correspondence to D.R. van der Westhuyzen, PhD, Department of Internal Medicine and Graduate Center for Nutritional Sciences, Wethington Health Sciences Building 541, 900 S Limestone St, Lexington, KY 40536. 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.

We investigated the atherogenic capability of circulating LDL from apoE-deficient mice and found that it functions in a proatherogenic manner, even without any further modification in vascular wall, through its uptake by scavenger receptors CD36 and SR-A.

Key Words: apolipoprotein E • macrophages • scavenger receptor • CD36 • SR-A

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