Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species.
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.
Podrez
E A
EA
Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Febbraio
M
M
Sheibani
N
N
Schmitt
D
D
Silverstein
R L
RL
Hajjar
D P
DP
Cohen
P A
PA
Frazier
W A
WA
Hoff
H F
HF
Hazen
S L
SL
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
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