Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species
Eugene A. Podrez, … , Henry F. Hoff, Stanley L. Hazen
Eugene A. Podrez, … , Henry F. Hoff, Stanley L. Hazen
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1095-1108. https://doi.org/10.1172/JCI8574.
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Article

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-H2O2-NO2–) system as a novel mechanism for converting LDL into a high-uptake form (NO2-LDL) for macrophages. We now identify the scavenger receptor CD36 as the major receptor responsible for high-affinity and saturable cellular recognition of NO2-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 NO2-LDL. Modification of LDL by the MPO-H2O2-NO2– 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 Cu2+-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 NO2-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

Eugene A. Podrez, Maria Febbraio, Nader Sheibani, David Schmitt, Roy L. Silverstein, David P. Hajjar, Peter A. Cohen, William A. Frazier, Henry F. Hoff, Stanley L. Hazen

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Figure 10

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Effect of lipid competitors on the binding of NO2-LDL to CD36-transfecte...
Effect of lipid competitors on the binding of NO2-LDL to CD36-transfected cells. [125I]LDL was modified as described for the complete system in Figure 2a. [125I]-NO2LDL (5 μg/mL) was then incubated with CD36-expressing 293 cells for 3 hours at 4°C in the presence of (a) 20 μg lipid/mL or (b) the indicated concentrations (μg lipid/mL) of competitors. PAPC, PAPC(SnCl2), PLPC, and POPC unilamellar vesicles were oxidized for 8 hours at 37°C as described for the complete system in Figure 2 in the presence (+NO2–, filled symbols) or absence (–NO2–, open symbols) of NO2–. Where indicated, BSA (0.2 mg protein/mL final concentration) was also included during liposome preparation as described in Methods (hatched bars). PAPC (SnCl2), hydroperoxide-free PAPC generated by reduction of PAPC with SnCl2, and then reisolation of PAPC under argon atmosphere before use were used as described in Methods. Data represent the mean ± SD of triplicate determinations (a) or means of triplicate determinations (b) of a representative experiment performed 3 times. AP < 0.001 for comparison versus control (no competitor).