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J. Biol. Chem., Vol. 282, Issue 11, 7817-7824, March 16, 2007

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Apolipoprotein E4 in Macrophages Enhances Atherogenesis in a Low Density Lipoprotein Receptor-dependent Manner^*

From the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525

Apolipoprotein E (apoE) and the low density lipoprotein receptor (LDLr) are well recognized determinants of atherosclerosis. In addition to hepatocytes, where both are highly expressed and contribute to plasma lipoprotein clearance, they are expressed in vascular cells and macrophages. In this study, we examined the effects of human apoE isoforms and LDLr levels in atherogenic pathways in primary macrophages ex vivo and atherosclerosis development after bone marrow transfer in vivo using mice expressing human apoE isoforms and different levels of LDLr expression. Increases in LDLr expression significantly increased cholesterol delivery into macrophages in culture, and the effects were more prominent with lipoproteins containing apoE4 than those containing apoE3. Conversely, increased LDLr expression reduced cholesterol efflux in macrophages expressing apoE4 but not in macrophages expressing apoE3. Furthermore, apoE3 protected VLDL from oxidation in vitro more than did apoE4. In LDLr-deficient mice expressing the human apoE4 isoform, Apoe^4/4 Ldlr^–/–, the replacement of bone marrow cells with those expressing LDLr increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLr. In contrast, atherosclerosis in Apoe^3/3 Ldlr^–/– mice, expressing the human apoE3 isoform, did not differ by the levels of macrophage LDLr expression. Our results demonstrate that apoE4, but not apoE3, in macrophages enhances atherosclerotic plaque development in mice in an LDLr-dependent manner and suggests that this interaction may contribute to the association of apoE4 with an increased cardiovascular risk in humans.

Received for publication, November 20, 2006 , and in revised form, December 26, 2006.

^* This work was supported by National Institutes of Health (NIH) Grant HL42630. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by NIH Grant T32HL69768.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of North Carolina, 701 Brinkhous-Bullitt Bldg., Chapel Hill, NC 27599-7525. Tel.: 919-966-6914; Fax: 919-966-8800; E-mail: nobuyo{at}med.unc.edu.

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