Effect of nitric oxide-donating agents on human monocyte cyclooxygenase-2.
COX-2 is involved in inflammation and ischemic cardiovascular disease. As NO regulates COX activity in various cells, we investigated the effect of NO-donors and the novel NO-aspirin NC-4016 on human monocyte COX-2. Whole blood was incubated with LPS and PGE(2) was measured in plasma as an index of monocyte COX-2 activity. Serum TxB(2) was assessed as an index of platelet COX-1 activity. SNP, DetaNONOate, and NO-aspirin inhibited dose-dependently PGE(2) production while aspirin was ineffective. The guanylyl-cyclase inhibitor ODQ partially reversed the suppression of COX-2 activity by NO-aspirin, demonstrating a role of cGMP increase. NC-4016 and aspirin inhibited platelet COX-1 comparably while NO-donors were ineffective. COX-2 expression was not affected by NO-donors or NO-aspirin while aspirin or the selective COX-2-inhibitor DUP697 increased it. In conclusion, Nitroaspirin inhibits monocyte COX-2 activity by a cGMP-dependent mechanism. This might represent an advantage over aspirin, given the possible detrimental role of COX-2 in cardiovascular disease.
Corazzi
Teresa
T
Section of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy.
Leone
Mario
M
Roberti
Rita
R
Del Soldato
Piero
P
Gresele
Paolo
P
D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*
D007527:Isoenzymes; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C102148:nitroaspirin; D001241:Aspirin