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Papers In Press, published online ahead of print February 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700410-JLR200

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Journal of Lipid Research, Vol. 49, 429-437, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Expression of the Lyst^beige mutation is atheroprotective in chow-fed apolipoprotein E-deficient mice

Ramona J. Petrovan^1,*, Yuan Yuan and Linda K. Curtiss^*

^* Department of Immunology, Scripps Research Institute, La Jolla, CA 92037
Division of Hematology and Oncology, New York University Medical Center, New York, NY 10016

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.

Published, JLR Papers in Press, November 2, 2007.

¹ To whom correspondence should be addressed. e-mail: rjpet{at}scripps.edu

Lyst^beige mice crossed with hyperlipidemic low density lipoprotein receptor-deficient mice (BgLDLr^–/–) display increased lesion area and a more stable lesion morphology. To verify that the beige phenotype is not unique to LDLr^–/– mice, we examined atherosclerosis in beige, apolipoprotein E-deficient mutant mice (BgApoE^–/–). Severe diet-induced hyperlipidemia in BgApoE^–/– mice resulted in increased aortic sinus lesion areas compared with controls. Minimal aortic lesions were observed in both genotypes on a chow diet. Nevertheless, BgApoE^–/– mice displayed drastically reduced aortic sinus lesion growth. Reconstitution with bone marrow (BM) from green fluorescent protein mice created chimeric animals that allowed for the identification of donor-derived cells within lesions. Expressing the beige mutation exclusively in BM-derived cells had no impact on plaque development, yet the beige mutation in all cells except the BM-derived cells led to significantly larger aortic sinus lesion areas. Both mRNA and secreted protein levels of monocyte chemoattractant protein 1 were altered in quiescent and phorbol ester-stimulated cultured macrophages, vascular smooth muscle cells, and aortic endothelial cells isolated from BgApoE^–/– mice. Thus, expression of the beige mutation in all cell types involved in lesion development contributed to atheroprotection in chow-fed ApoE^–/– mice.

Supplementary key words low density lipoprotein receptor-deficient mice • bone marrow transplantation • plaque • macrophage

Abbreviations: ApoE^–/–, apolipoprotein E-deficient; BgApoE^–/–, Lyst^beige mice crossed with apolipoprotein E-deficient mice; BM, bone marrow; BMT, bone marrow transplantation; DAPI, 4',6-diamino-phenylindole; EC, endothelial cell; GFP, green fluorescent protein; HFD, high-fat diet; LDLr, low density lipoprotein receptor; MCP-1, monocyte chemoattractant protein 1; PMA, phorbol ester; SMC, smooth muscle cell

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