Expression of the Lyst(beige) mutation is atheroprotective in chow-fed apolipoprotein E-deficient mice.
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.
Petrovan
Ramona J
RJ
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA. rjpet@scripps.edu
Yuan
Yuan
Y
Curtiss
Linda K
LK
D000821:Animal Feed; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D033921:Vesicular Transport Proteins
D001057:Apolipoproteins E; D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D011506:Proteins; D011973:Receptors, LDL; D033921:Vesicular Transport Proteins