Submitted on September 11, 2007
Revised on November 1, 2007
Accepted on November 2, 2007
Expression of the Lystbeige mutation is atheroprotective in chow-fed apolipoprotein E-deficient mice
Ramona J. Petrovan, Yuan Yuan, and Linda K. Curtiss
Immunology, The Scripps Research Institute, La Jolla, CA 92037
Corresponding Author: rjpet{at}scripps.edu
Lystbeige mice crossed with LDL receptor-deficient mice (BgLDLr-/-) display increased lesion area and a more stable lesion morphology compared to LDLr-/- mice when fed a pro-atherogenic high fat diet. To verify that the beige phenotype is not unique to LDLr-/- mice, we examined atherosclerosis in beige, apolipoprotein E-deficient mutant mice (BgApoE-/-). Consistent with findings in the LDLr-/- background, severe diet-induced hyperlipidemia in BgApoE-/- mice resulted in a marked increase in the extent of the aortic sinus lesion areas compared to controls. When fed a chow diet, only minimal aortic lesions were observed in both genotypes. Nevertheless, BgApoE-/- mice displayed a drastically reduced aortic sinus lesion growth. Reconstitution with bone marrow (BM) from GFP, ApoE-/- mice or GFP, BgApoE-/- mice in two bone marrow transplantation (BMT) studies created chimeric mice with green fluorescent protein (GFP) in BM-derived cells, allowing direct identification of donor-derived cells within the lesions. Expressing the beige mutation exclusively in BM-derived cells had no impact on plaque development. However, expressing the beige mutation in all cells except the BM-derived cells lead to aortic sinus lesion areas that were significantly larger in the chow-fed mice. Moreover, both mRNA and secreted protein levels of monocyte chemoattractant protein 1 (MCP-1) were altered in quiescent and PMA-stimulated cultured BM-derived macrophages, vascular smooth muscle cells and aortic endothelial cells isolated from BgApoE-/- mice. These results suggest that expression of the beige mutation in all cell types involved in lesion development contribute to the atheroprotective effect in chow-fed ApoE-/- mice.
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