title: COX-2 is not involved in thromboxane biosynthesis by activated human platelets.
abstract: The occurrence of aspirin resistance has been inferred by the assessment of platelet aggregation ex vivo in patients with ischemic vascular syndromes taking aspirin. Since aspirin is a weak inhibitor of the inducible isoform of prostaglandin H synthase (COX-2), it was suggested that COX-2 may play a role in aspirin resistance. However the cellular source(s) of COX-2 possibly responsible for aspirin resistance remains unknown. Recently, the expression of the inducible isoform of COX-2 in circulating human platelets was reported. To investigate the possible contribution of COX-2 expression in platelet thromboxane (TX) biosynthesis, we have compared the inhibitory effects of NS-398 and aspirin, selective inhibitors of COX-2 and COX-1, respectively, on prostanoid biosynthesis by thrombin-stimulated platelets vs lipopolysaccharide (LPS)stimulated monocytes (expressing high levels of COX-2) isolated from whole blood of healthy subjects. NS-398 was 180-fold more potent in inhibiting monocyte COX-2 activity than platelet TXB2 production. In contrast, aspirin (55 micromol/L) largely suppressed platelet TXB2 production without affecting monocyte COX-2 activity. By using specific Western blot techniques, we failed to detect COX-2 in platelets while COX-1 was readily detectable. Our results argue against the involvement of COX-2 in TX biosynthesis by activated platelets and consequently dispute platelet COX-2 expression as an important mechanism of aspirin resistance.
authors.affiliation: Department of Medicine and Aging, G. D'Annunzio University of Chieti, School of Medicine, Italy. ppatrignani@unich.it
authors.forename: P
authors.initials: P
authors.lastname: Patrignani
authors.forename: M G
authors.initials: MG
authors.lastname: Sciulli
authors.forename: S
authors.initials: S
authors.lastname: Manarini
authors.forename: G
authors.initials: G
authors.lastname: Santini
authors.forename: C
authors.initials: C
authors.lastname: Cerletti
authors.forename: V
authors.initials: V
authors.lastname: Evangelista
mesh_terms: D000328:Adult; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D009000:Monocytes / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D015539:Platelet Activation; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis*; D020033:Protein Isoforms; D013449:Sulfonamides / Q000494:pharmacology; D013931:Thromboxanes / Q000096:biosynthesis*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D020033:Protein Isoforms; D013449:Sulfonamides; D013931:Thromboxanes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin