title: A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions.
abstract: The macrophage scavenger receptor CD36 plays an important role in binding and uptake of oxidized forms of low-density lipoprotein (LDL), foam cell formation, and lesion development during atherosclerosis. The structural basis of CD36-lipoprotein ligand recognition is an area of intense interest. In a companion article we reported the characterization of a structurally conserved family of oxidized choline glycerophospholipids (oxPC(CD36)) that serve as novel high affinity ligands for cells stably transfected with CD36, mediating recognition of multiple oxidized forms of LDL (Podrez, E. A., Poliakov, E., Shen, Z., Zhang, R., Deng, Y., Sun, M., Finton, P., Shan, L., Gugiu, B., Fox, P. L., Hoff, H. F., Salomon, R. G., and Hazen, S. L. (July 8, 2002) J. Biol. Chem. 277, 10.1074/jbc.M203318200). Here we use macrophages from wild-type and CD36 null mice to demonstrate that CD36 is the major receptor on macrophages mediating recognition of oxPC(CD36) species when presented (+/- plasma) in pure form, within PC bilayers in small unilamellar vesicles, and within liposomes generated from lipid extracts of native LDL. We also show that oxPC(CD36) promote CD36-dependent recognition when present at only a few molecules per particle, resulting in macrophage binding, uptake, metabolism, cholesterol accumulation, and foam cell formation. Finally, using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS), we demonstrate that oxPC(CD36) are generated in vivo and are enriched in atherosclerotic lesions. Collectively, our data suggest that formation of this novel family of oxidized phospholipids participates in CD36-mediated recognition of oxidized lipoproteins and foam cell formation in vivo.
authors.affiliation: Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
authors.forename: Eugenia
authors.initials: E
authors.lastname: Poliakov
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Shen
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Sun
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Finton
authors.forename: Lian
authors.initials: L
authors.lastname: Shan
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: David P
authors.initials: DP
authors.lastname: Hajjar
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: Henry F
authors.initials: HF
authors.lastname: Hoff
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000473:pathology*; D018955:CD36 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D011817:Rabbits; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D008081:Liposomes; D010743:Phospholipids; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D002784:Cholesterol