Peroxynitrite stimulates the activity of cytosolic phospholipase A2 in U937 cells: the extent of arachidonic acid formation regulates the balance between cell survival or death.
Peroxynitrite stimulates in U937 cells release of arachidonic acid (AA) sensitive to various phospholipase A(2) (PLA(2)) inhibitors, including arachidonyl trifluoromethyl ketone (AACOCF(3)), which specifically inhibits cytosolic PLA(2) (cPLA(2)). This response linearly increases using non toxic concentrations of the oxidant, and reaches a plateau at levels at which toxicity becomes apparent. Three separate lines of evidence are consistent with the notion that AA generated by cPLA(2) promotes survival in cells exposed to peroxynitrite. Firstly, toxicity was suppressed by nanomolar levels of exogenous AA, or by AA generated by the direct PLA(2) activator melittin. Secondly AACOCF(3), or other PLA(2) inhibitors, promoted cell death after exposure to otherwise non toxic concentrations of peroxynitrite; exogenous AA abolished the enhancing effects mediated by the PLA(2) inhibitors. Finally, U937 cells transfected with cPLA(2) antisense oligonucleotides were killed by concentrations of peroxynitrite that were non-toxic for cells transfected with nonsense oligonucleotides. This lethal response was insensitive to AACOCF(3) and prevented by exogenous AA.
Tommasini
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Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Via S Chiara, 27 - 61029 Urbino (PU), Italy.
Sestili
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P
Guidarelli
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Cantoni
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O
D016718:Arachidonic Acid / Q000096:biosynthesis*; D001095:Arachidonic Acids / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005057:Eukaryotic Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D010741:Phospholipases A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; C081565:arachidonyltrifluoromethane; D030421:Peroxynitrous Acid; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2