Apoptosis induced by oxidized low density lipoprotein in human monocyte-derived macrophages involves CD36 and activation of caspase-3

Eur J Biochem. 2000 Oct;267(19):6050-9. doi: 10.1046/j.1432-1327.2000.01682.x.

Abstract

Macrophage death may play a crucial role in the progression of atherosclerotic lesions. Here we present evidence that CD36 is involved in oxidized LDL (OxLDL)-induced apoptosis in human monocyte-derived macrophages. Anti-CD36 mAb SMO and OKM-5 reduced the number of apoptotic cells in OxLDL-treated macrophages by more than 94%, but they did not block ceramide-triggered apoptosis. Thrombospondin inhibited the induction of apoptosis by OxLDL in a dose-dependent manner with an IC50 of 10-30 microM. OxLDL did not induce apoptosis in CD36-negative macrophages, demonstrating the essential role of this scavenger receptor in OxLDL-triggered programmed cell death. Neither anti-CD36 Ig nor thrombospondin triggered programmed cell death suggesting that binding to CD36 alone is not sufficient to initiate apoptosis. However, inhibitors of OxLDL-induced apoptosis did not block the uptake of 3H-labeled OxLDL. In contrast, acetylated LDL and polyinosinic acid, ligands of scavenger receptor A (SRA), inhibited uptake of 3H-labeled OxLDL by 65 and 49%, respectively, but did not block OxLDL-induced apoptosis, indicating that SRA is not involved in this process. OxLDL also stimulated caspase-3 activity in human macrophages. Activation of caspase-3 was blocked by anti-CD36 Ig and the caspase-3 inhibitor Z-DEVD-FMK. These results suggest that binding of OxLDL to CD36 initiates a yet unknown OxLDL-specific signaling event, which leads to the rapid activation of caspase-3 resulting in apoptosis of human macrophages. Our data demonstrate a novel role for CD36 in macrophage biology with likely consequences for the development of atherosclerotic lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects*
  • Blood Physiological Phenomena
  • CD36 Antigens / immunology
  • CD36 Antigens / physiology*
  • Caspase 3
  • Caspases / physiology*
  • Cell Differentiation
  • Cells, Cultured
  • Ceramides / physiology
  • Culture Media / pharmacology
  • Culture Media, Serum-Free / pharmacology
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA / analysis
  • Enzyme Activation
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Lipoproteins, LDL / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Monocytes / cytology
  • Oligopeptides / pharmacology
  • Poly I / pharmacology
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / drug effects
  • Receptors, Immunologic / physiology*
  • Receptors, Scavenger
  • Thrombospondins / pharmacology

Substances

  • Amino Acid Chloromethyl Ketones
  • Antibodies, Monoclonal
  • CD36 Antigens
  • Ceramides
  • Culture Media
  • Culture Media, Serum-Free
  • Cysteine Proteinase Inhibitors
  • Lipoproteins, LDL
  • Oligopeptides
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Thrombospondins
  • acetyl-LDL
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • oxidized low density lipoprotein
  • Poly I
  • DNA
  • CASP3 protein, human
  • Caspase 3
  • Caspases