Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent

Abstract

Oxidized low density lipoprotein (oxLDL) induces apoptosis in human macrophages (MΦ), a significant feature in atherogenesis. We found that induction of apoptosis in MΦ by oxLDL, C 2 ‐ceramide, tumor necrosis factor α (TNF‐α), and hydrogen peroxide (H 2 O 2 ) was associated with enhanced expression of manganese superoxide dis‐mutase (MnSOD) and p53. Treatment of cells with p53 or MnSOD antisense oligonucleotides prior to stimulation with oxLDL, C 2 ‐ceramide, TNF‐α, or H 2 O 2 caused an inhibition of the expression of the respective protein together with a marked reduction of apoptosis. Exposure to N‐acetylcysteine before treatment with oxLDL, C 2 ‐ceramide, TNF‐α, or H 2 O 2 reversed a decrease in cellular glutathione concentrations as well as the enhanced production of p53 and MnSOD mRNA and protein. In apoptotic macrophages of human atherosclerotic plaques, colocalization of MnSOD and p53 immunoreactivity was found. These results indicate that in oxLDL‐induced apoptosis, a concomitant induction of p53 and MnSOD is critical, and suggest that it is at least in part due to an enhancement of the sphingomyelin/ ceramide pathway.—Kinscherf, R., Claus, R., Wagner, M., Gehrke, C., Kamencic, H., Hou, D., Nauen, O., Schmiedt, W., Kovacs, G., Pill, J., Metz, J., Deigner, H.‐P. Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J . 12, 461–467 (1998)