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* Institute of Pharmaceutical Chemistry and Clinics of Anaesthesiology and Intensive Care Medicine, Jena, Germany,
Department of Anatomy and Cell Biology III, and the
Institute of Pathochemistry and Neurochemistry, University of Heidelberg, 69120 Heidelberg, Germany
1Correspondence: Clinics of Anaesthesiology and Intensive Care Medicine, University of Jena, 07740 Jena, Germany. E-mail: hans-peter.deigner{at}med.uni-jena.de
Sphingomyelinase (SMase) stimulation and subsequent ceramide generation
are suggested to be involved in signal transduction of stress-induced
apoptosis. We now show that apoptosis of human macrophages (M
) and
fibroblasts initiated by oxidized low density lipoproteins (minimally
modified LDL, mmLDL) is associated with an increase in acid SMase
(aSMase, E.C. 3.1.4.12) expression and ceramide concentration.
Application of a novel, potent, and specific inhibitor of aSMase
expression (NB6) diminished the effects of mmLDL and
C6-ceramide treatment by inhibiting transcription via Sp1
and AP-2. Moreover, apoptosis was abolished after mmLDL and
C6-ceramide treatment of hereditary aSMase-deficient
fibroblasts (from Niemann-Pick patients). We suggest 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.—Deigner, H.-P.,
Claus, R., Bonaterra, G. A., Gehrke, C., Bibak, N., Blaess, M.,
Cantz, M., Metz, J., Kinscherf, R. Ceramide induces aSMase expression:
implications for oxLDL-induced apoptosis.
Key Words: acid sphingomyelinase • macrophages • Niemann-Pick • programmed cell death • C6-ceramide
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