Regulation of prostaglandin H2 synthase activity by nitrogen oxides.
Nitric oxide and its derivatives have been shown to both activate and inhibit prostaglandin H(2) synthase 1 (PGHS-1). We set out to determine the mechanisms by which different nitrogen oxide derivatives modulate PGHS-1 activity. To this end, we show that 3-morpholinosydnonimine hydrochloride (SIN-1), a compound capable of generating peroxynitrite, activates purified PGHS-1 and also stimulates PGE(2) production in arterial smooth muscle cells in the presence of exogenous arachidonic acid. The effect of SIN-1 in smooth muscle cells was abrogated by superoxide and peroxynitrite inhibitors, which supports the hypothesis that peroxynitrite is an activating species of PGHS-1. Indeed, authentic peroxynitrite also induced PGE(2) production in arachidonic acid-stimulated cells. In contrast, when cells were exposed to the nitric oxide-releasing compound 1-hydroxy-2-oxo-3-[(methylamino)propyl]-3-methyl-1-triazene (NOC-7), PGHS-1 enzyme activity was inhibited in the presence of exogenous arachidonic acid. Finally, in lipid-loaded smooth muscle cells, we demonstrate that SIN-1 stimulates arachidonic acid-induced PGE(2) production; albeit, the extent of activation is reduced compared to that under normal conditions. These results indicate that formation of peroxynitrite is a key intermediary step in PGHS-1 activation. However, other forms of NO(x)() inhibit PGHS-1. These results may have implications in the regulation of vascular function and tone in normal and atherosclerotic arteries.
Upmacis
R K
RK
Department of Biochemistry, Center of Vascular Biology, Joan and Sanford I. Weill Medical College of Cornell University, New York 10021, USA. rupmacis@mail.med.cornell.edu
Deeb
R S
RS
Hajjar
D P
DP
D000818:Animals; D001013:Aorta, Thoracic; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism; D006834:Hydrazines / Q000378:metabolism; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008981:Molsidomine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine; D012756:Sheep; D013481:Superoxides / Q000378:metabolism
C115239:3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006834:Hydrazines; D007527:Isoenzymes; D008565:Membrane Proteins; D009566:Nitrates; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010545:Peroxides; D011448:Prostaglandin Antagonists; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D010396:Penicillamine