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 pi votal event in the development of cardiovascular disease. Recent studies ha ve identified reactive nitrogen species generated by monocytes by way of th e myeloperoxidase-hydrogen peroxide-nitrite (MPO-H2O2-NO2-) system as a nov el mechanism for converting LDL into a high-uptake form (NO2-LDL) for macro phages. We now identify the scavenger receptor CD36 as the major receptor r esponsible 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 CD3 6-dependent binding, cholesterol loading, and macrophage foam cell formatio n after exposure to NO2-LDL. Modification of LDL by the MPO-H2O2-NO2- syste m in the presence of up to 80% lipoprotein-deficient serum (LPDS) still res ulted in the conversion of the lipoprotein into a high-uptake form for macr ophages, whereas addition of less than 5% LPDS totally blocked Cu2+-catalyz ed LDL oxidation and conversion into a ligand for CD36. Competition studies demonstrated that lipid oxidation products derived from 1-palmitoyl-2-arac hidonyl-sn-glycero-3-phosphocholine can serve as essential moieties on NO2- LDL recognized by CD36. Collectively, these results suggest that MPO-depend ent conversion of LDL into a ligand for CD36 is a likely pathway for genera ting foam cells in vivo. MPO secreted from activated phagocytes may also ta g phospholipid-containing targets for removal by CD36-positive cells.