Differential modulation of prostaglandin H synthase-2 by nitric oxide-related species in intact cells.
Nitrogen monoxide (NO) has been reported to both activate and inhibit prostaglandin (PG) biosynthesis. This apparent paradox might be explained by the production/action of distinct NO-related species formed as a result of the prevailing redox states of different cellular systems. As such, the effect of NO donors with different redox characteristics on the modulation of prostaglandin H synthase-2 (PGHS-2) in primary mouse cortical astrocytes and COS-7 cells engineered to overexpress PGHS-2 was assessed. In general, compounds that released NO(*) or NO(-) enhanced, while a peroxynitrite (OONO(-)) generator inhibited, PGHS-2-dependent prostaglandin production. While the possibility of altered gene transcription was eliminated in the COS-7 system as PGHS-2 was maximally expressed, in primary astrocytes where PGHS-2 expression was induced by lipopolysaccharide (LPS), effects on protein expression were detected. Compounds that released NO(*) synergistically enhanced LPS-mediated PGHS-2 protein synthesis. None of these effects were mediated by cGMP. All donors lost their ability to modulate PGHS-2 expression and function when decayed. These results indicate that the ultimate effect of NO on PGHS-2 enzyme activity and expression is dictated by the prevalent NO-related species formed, suggesting that important interactions which may exist between NO and prostanoid pathways in vivo will be highly dependent on the inherent redox environment.
Vidwans
A S
AS
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030-3401, USA.
Uliasz
T F
TF
Hewett
J A
JA
Hewett
S J
SJ
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D001921:Brain / Q000201:enzymology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine; D014162:Transfection
D007527:Isoenzymes; D008070:Lipopolysaccharides; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010396:Penicillamine; D015232:Dinoprostone