Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis

Sphingomyelinase (SMase) stimulation and subsequent ceramide generation are suggested to be involved in signal transduction of stress-induced apoptosi s, We now show that apoptosis of human macrophages (M phi) and fibroblasts initiated by oxidized low density lipoproteins (minimally modified LDL, mmL DL) is associated with an increase in acid SMase (aSMase, E.C, 3.1.4.12) ex pression and ceramide concentration. Application of a novel, potent, and sp ecific inhibitor of aSMase expression (NB6) diminished the effects of mmLDL and C-6-ceramide treatment by inhibiting transcription via Sp1 and AP-2. M oreover, apoptosis was abolished after mmLDL and C-6-ceramide treatment of hereditary aSMase-deficient fibroblasts (from Niemann-Pick patients), We su ggest that in mmLDL-initiated apoptosis 1) enhanced ceramide generation via aSMase appears to be required as well as 2) a positive feedback control of aSMase expression by the increase in intracellular ceramide concentration.