title: Nitric oxide inhibits APO-1/Fas-mediated cell death.
abstract: Activation of the cysteine protease caspases, which are homologous to the product of Caenorhabditis elegans cell-death gene ced 3, is required to mediate APO-1/Fas-induced apoptosis. We report here that nitric oxide (NO) released by exogenous NO donors, as well as NO endogenously derived by transfection with the inducible NO synthase, substantially suppresses APO-1/Fas-triggered cell death of Jurkat cells. The inhibitory NO effect was independent of cGMP, because 8-bromo-cGMP did not influence APO-1/Fas-mediated apoptosis. In contrast, NO interferes with the APO-1/Fas-induced stimulation of caspases. NO inhibits the proteolytic cleavage of caspase-3 (CPP32) into its active subunits, thereby suppressing caspase-3 activity. In addition, NO potently inhibits apoptosis induction by overexpresssion of the death domain protein FADD or the immediate downstream target caspase-8. These results suggest that NO modulates the proteolytic cascade upstream of caspase-3. Indeed, NO specifically S-nitrosylates caspase-8 and caspase-1 and thereby may prevent activation of the proteolytic cascade. The NO-mediated increase in the resistance toward induction of apoptosis may play a major role in mediating immune responses, as well as in the pathogenesis of autoimmune diseases.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Dimmeler
authors.forename: J
authors.initials: J
authors.lastname: Haendeler
authors.forename: A
authors.initials: A
authors.lastname: Sause
authors.forename: A M
authors.initials: AM
authors.lastname: Zeiher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053200:Fas-Associated Death Domain Protein; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D026422:S-Nitrosoglutathione; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D009603:Nitroso Compounds; D011500:Protein Synthesis Inhibitors; C110881:S-nitro-N-acetylpenicillamine; D019014:fas Receptor; D009599:Nitroprusside; D003609:Dactinomycin; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D003513:Cycloheximide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D005978:Glutathione; D010396:Penicillamine