Expression of the Lystbeige mutation is atheroprotective in chow-fed apolipoprotein E-deficient mices⃞

Abstract

Lystbeige 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.

Keywords

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