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

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 µm. 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.