US EPA

156780 

Journal Article 

Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice 

Moore, KJ; Kunjathoor, VV; Koehn, SL; Manning, JJ; Tseng, AA; Silver, JM; McKee, M; Freeman, MW 

2005 

Yes 

Journal of Clinical Investigation
ISSN: 0021-9738
EISSN: 1558-8238 

115 

2192-2201 

Macrophage internalization of modified lipoproteins is thought to play a critical roll in the initiation of atherogenesis. Two scavenger receptors, scavenger receptor A (SR-A) and CD36, have been centrally implicated in this lipid uptake process. Previous studies showed that these receptors mediated the majority of cholesterol ester accumulation in macrophages exposed to oxidized LDL and that mice with deletions of either receptor exhibited marked reductions in atherosclerosis. This work has contributed to an ather asclerosis paradigm: scavenger receptor-mediated oxidized lipoprotein uptake is required for foam cell for nation and atherogenesis. In this study, Apoe-/- mice lacking SR-A or CD36, backcrossed into the C57BL/6 str ain for 7 generations, were fed an atherogenic diet for 8 weeks. Hyperlipidemic Cd36-/-Apoe-/- and Msr1-/-Apoe-/- mice showed significant reductions in peritoneal macrophage lipid accumulation in vivo; however, in contrast with previous reports, this was associated with increased aortic sinus lesion areas. Characterization of aort ic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, i ndicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A. These data show that alternative lipid uptake mechanisms may contribute to macrophage cholesterol ester accumulation in vivo and suggest that the roles of SR-A and CD36 as proatherosclerotic mediators of modified LDL uptake in vivo need to be reassessed.