Bcl-2 protein inhibits oxysterol-induced apoptosis through suppressing CPP32-mediated pathway.
Oxysterols are presumed to mediate cytotoxicity of oxidized LDL in atherosclerotic lesions. To elucidate its molecular mechanism, we established murine macrophage-like P388-D1 cells which over-express Bcl-2 protein by retrovirus-mediated gene transfer. Oxysterols (7-ketocholesterol, 25-hydroxycholesterol) induced nuclear condensation and oligonucleosomal DNA fragmentation, which were partially inhibited by Bcl-2 over-expression. Though CPP32 inhibitor suppressed the cell death in control cells, it showed no additive protection in the cells over-expressing Bcl-2. These findings indicate that oxysterols induce apoptosis via Bcl-2-inhibitable and -uninhibitable pathways, and the former depends on CPP32 activation.
Harada
K
K
Third Department of Internal Medicine, University of Tokyo, Bunkyo-Ku, Japan.
Ishibashi
S
S
Miyashita
T
T
Osuga
J
J
Yagyu
H
H
Ohashi
K
K
Yazaki
Y
Y
Yamada
N
N
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007653:Ketocholesterols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C007997:25-hydroxycholesterol; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; C003001:7-ketocholesterol