Macrophage Scavenger Receptor CD36 Is the Major Receptor for LDL Modified by Monocyte-Generated Reactive Nitrogen Species

J Clin Invest. 2000 Apr;105(8):1095-108. doi: 10.1172/JCI8574.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD36 Antigens / metabolism*
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Glucose Oxidase / metabolism
  • Humans
  • Hydrogen Peroxide / metabolism
  • Ligands
  • Lipoproteins, LDL / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology
  • Monocytes / metabolism*
  • Nitrogen Dioxide / metabolism*
  • Peroxidase / metabolism
  • Receptors, Immunologic / metabolism*
  • Receptors, LDL / metabolism*
  • Receptors, Scavenger
  • Time Factors

Substances

  • CD36 Antigens
  • Ligands
  • Lipoproteins, LDL
  • Receptors, Immunologic
  • Receptors, LDL
  • Receptors, Scavenger
  • oxidized low density lipoprotein
  • Hydrogen Peroxide
  • Glucose Oxidase
  • Peroxidase
  • Nitrogen Dioxide