title: Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice.
abstract: Macrophage internalization of modified lipoproteins is thought to play a critical role 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 atherosclerosis paradigm: scavenger receptor-mediated oxidized lipoprotein uptake is required for foam cell formation and atherogenesis. In this study, Apoe-/- mice lacking SR-A or CD36, backcrossed into the C57BL/6 strain 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 aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating 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.
authors.affiliation: Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Vidya V
authors.initials: VV
authors.lastname: Kunjathoor
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Koehn
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Manning
authors.forename: Anita A
authors.initials: AA
authors.lastname: Tseng
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Silver
authors.forename: Mary
authors.initials: M
authors.lastname: McKee
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D004036:Diet, Atherogenic; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D012850:Sinus of Valsalva / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; C495140:Msr1 protein, mouse; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein