APOPTOSIS CAUSED BY OXIDIZED LDL IS MANGANESE SUPEROXIDE-DISMUTASE AND P53 DEPENDENT

Oxidized low density lipoprotein (oxLDL) induces apoptosis in human ma crophages (M Phi), a significant feature in atherogenesis. We found th at induction of apoptosis in M Phi by oxLDL, C-2-ceramide, tumor necro sis factor alpha (TNF-alpha), and hydrogen peroxide (H2O2) was associa ted with enhanced expression of manganese superoxide dismutase (MnSOD) and p53. Treatment of cells with p53 or MnSOD antisense oligonucleoti des prior to stimulation with oxLDL, C-2-ceramide, TNF-alpha, or H2O2 caused an inhibition of the expression of the respective protein toget her with a marked reduction of apoptosis. Exposure to N-acetylcysteine before treatment with oxLDL, C-2-ceramide, TNF-alpha, or H2O2 reverse d a decrease in cellular glutathione concentrations as well as the enh anced production of p53 and MnSOD mRNA and protein. In apoptotic macro phages of human atherosclerotic plaques, colocalization of MnSOD and p 53 immunoreactivity was found. These results indicate that in oxLDL-in duced 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.