This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/1/168    most recent 01.ATV.0000149145.00865.d9v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhao, Z. Articles by van der Westhuyzen, D. R. Search for Related Content PubMed PubMed Citation Articles by Zhao, Z. Articles by van der Westhuyzen, D. R.

(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

This article has been cited by other articles:

				B. Boyanovsky, M. Zack, K. Forrest, and N. R. Webb The Capacity of Group V sPLA2 to Increase Atherogenicity of ApoE-/- and LDLR-/- Mouse LDL In Vitro Predicts its Atherogenic Role In Vivo Arterioscler. Thromb. Vasc. Biol., April 1, 2009; 29(4): 532 - 538. [Abstract] [Full Text] [PDF]

				S. Kuchibhotla, D. Vanegas, D. J. Kennedy, E. Guy, G. Nimako, R. E. Morton, and M. Febbraio Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II Cardiovasc Res, April 1, 2008; 78(1): 185 - 196. [Abstract] [Full Text] [PDF]

				D. Wu, C. Sharan, H. Yang, J. S. Goodwin, L. Zhou, G. A. Grabowski, H. Du, and Z. Guo Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages J. Lipid Res., December 1, 2007; 48(12): 2571 - 2578. [Abstract] [Full Text] [PDF]

				Y.-L. Lin, W. J. S. de Villiers, B. Garvy, S. R. Post, T. R. Nagy, F. F. Safadi, M. C. Faugere, G. Wang, H. H. Malluche, and J. P. Williams The Effect of Class A Scavenger Receptor Deficiency in Bone J. Biol. Chem., February 16, 2007; 282(7): 4653 - 4660. [Abstract] [Full Text] [PDF]

				A. Handberg, K. Levin, K. Hojlund, and H. Beck-Nielsen Identification of the Oxidized Low-Density Lipoprotein Scavenger Receptor CD36 in Plasma: A Novel Marker of Insulin Resistance Circulation, September 12, 2006; 114(11): 1169 - 1176. [Abstract] [Full Text] [PDF]

				C. A. Beamer and A. Holian Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L186 - L195. [Abstract] [Full Text] [PDF]