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 11

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Effect of oxidized PAPC vesicles on the binding of NO2-LDL to hMDM and M...
Effect of oxidized PAPC vesicles on the binding of NO2-LDL to hMDM and MPM. [125I]LDL was modified as described for the complete system in Figure 2. [125I]NO2-LDL (5 μg/mL) was then incubated with (a) MPM or with (b) hMDM for 3 hours at 4°C either in the absence (NA) or presence of the indicated additions. Cellular binding of lipoproteins was subsequently determined as described in Methods. The concentrations of competitors used were 200 μg protein/mL for lipoproteins, 20 μg lipid/mL for vesicles, and 20 μg/mL for antibody. NO2-LDL, LDL modified by the MPO-H2O2-NO2– system as in the complete system of Figure 2a; –NO2LDL, LDL modified by the MPO-H2O2 system but in the absence of NO2–; NO2-PAPC, PAPC vesicles modified by the complete MPO-H2O2-NO2– system; –NO2 PAPC, PAPC modified by the MPO-H2O2 system but in the absence of NO2–. Data represent the mean ± SD of triplicate determinations of a representative experiment performed at least 3 times. AP < 0.001 for comparison versus control (NA).