title: Apoptosis induced by oxidized low density lipoprotein in human monocyte-derived macrophages involves CD36 and activation of caspase-3.
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.
authors.affiliation: Institute of Biochemistry and Institute of Anatomy, University of Basel, Switzerland.
authors.forename: E S
authors.initials: ES
authors.lastname: Wintergerst
authors.forename: J
authors.initials: J
authors.lastname: Jelk
authors.forename: C
authors.initials: C
authors.lastname: Rahner
authors.forename: R
authors.initials: R
authors.lastname: Asmis
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001790:Blood Physiological Phenomena; D018955:CD36 Antigens / Q000276:immunology / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002518:Ceramides / Q000502:physiology; D003470:Culture Media / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D004789:Enzyme Activation; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000166:cytology; D009842:Oligopeptides / Q000494:pharmacology; D011069:Poly I / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D051116:Receptors, Scavenger; D019699:Thrombospondins / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D002518:Ceramides; D003470:Culture Media; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D008077:Lipoproteins, LDL; D009842:Oligopeptides; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D019699:Thrombospondins; C032629:acetyl-LDL; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C099252:oxidized low density lipoprotein; D011069:Poly I; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases