title: Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species.
abstract: The oxidative conversion of LDL into an atherogenic form is considered a pivotal event in the development of cardiovascular disease. Recent studies have identified reactive nitrogen species generated by monocytes by way of the myeloperoxidase-hydrogen peroxide-nitrite (MPO-H(2)O(2)-NO(2)(-)) system as a novel mechanism for converting LDL into a high-uptake form (NO(2)-LDL) for macrophages. We now identify the scavenger receptor CD36 as the major receptor responsible for high-affinity and saturable cellular recognition of NO(2)-LDL by murine and human macrophages. Using cells stably transfected with CD36, CD36-specific blocking mAbs, and CD36-null macrophages, we demonstrated CD36-dependent binding, cholesterol loading, and macrophage foam cell formation after exposure to NO(2)-LDL. Modification of LDL by the MPO-H(2)O(2)-NO(2)(-) system in the presence of up to 80% lipoprotein-deficient serum (LPDS) still resulted in the conversion of the lipoprotein into a high-uptake form for macrophages, whereas addition of less than 5% LPDS totally blocked Cu(2+)-catalyzed LDL oxidation and conversion into a ligand for CD36. Competition studies demonstrated that lipid oxidation products derived from 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine can serve as essential moieties on NO(2)-LDL recognized by CD36. Collectively, these results suggest that MPO-dependent conversion of LDL into a ligand for CD36 is a likely pathway for generating foam cells in vivo. MPO secreted from activated phagocytes may also tag phospholipid-containing targets for removal by CD36-positive cells.
authors.affiliation: Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Podrez
authors.forename: M
authors.initials: M
authors.lastname: Febbraio
authors.forename: N
authors.initials: N
authors.lastname: Sheibani
authors.forename: D
authors.initials: D
authors.lastname: Schmitt
authors.forename: R L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: D P
authors.initials: DP
authors.lastname: Hajjar
authors.forename: P A
authors.initials: PA
authors.lastname: Cohen
authors.forename: W A
authors.initials: WA
authors.lastname: Frazier
authors.forename: H F
authors.initials: HF
authors.lastname: Hoff
authors.forename: S L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D005949:Glucose Oxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009585:Nitrogen Dioxide / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D051116:Receptors, Scavenger; D013997:Time Factors
chemical_list: D018955:CD36 Antigens; D008024:Ligands; D008077:Lipoproteins, LDL; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D009195:Peroxidase; D009585:Nitrogen Dioxide