title: Aspirin induces platelet receptor shedding via ADAM17 (TACE).
abstract: Aspirin is effective in the therapy of cardiovascular diseases, because it causes acetylation of cyclooxygenase 1 (COX-1) leading to irreversible inhibition of platelets. Additional mechanisms can be suspected, because patients treated with other platelet COX inhibitors such as indomethacin do not display an increased bleeding tendency as observed for aspirin-treated patients. Recently, aspirin and other anti-inflammatory drugs were shown to induce shedding of L-selectin in neutrophils in a metalloproteinase-dependent manner. Therefore, we investigated the effects of aspirin on the von Willebrand Factor receptor complex glycoprotein (GP) Ib-V-IX, whose lack or dysfunction causes bleeding in patients. As quantified by fluorescence-activated cell sorting analysis in whole blood, aspirin, but not its metabolite salicylic acid, induced dose-dependent shedding of human and murine GPIbalpha and GPV from the platelet surface, whereas other glycoproteins remained unaffected by this treatment. Biotinylated fragments of GPV were detected by immunoprecipitation in the supernatant of washed mouse platelets, and the expression level of GPIbalpha was decreased in these platelets as measured by Western blot analysis. Although shedding occurred normally in COX-1-deficient murine platelets, shedding was completely blocked by a broad-range metalloproteinase inhibitor and, more importantly, in mouse platelets expressing an inactive form of ADAM17. Shed fragments of GPIbalpha and GPV were elevated in the plasma of aspirin-injected mice compared with animals injected with control buffer. These data demonstrate that aspirin at high concentrations induces shedding of GPIbalpha and GPV by an ADAM17-dependent mechanism and that this process can occur in vivo.
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Versbacherstrasse 9, 97078 Würzburg, Germany.
authors.forename: Barsom
authors.initials: B
authors.lastname: Aktas
authors.forename: Miroslava
authors.initials: M
authors.lastname: Pozgajova
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
authors.forename: Susan
authors.initials: S
authors.lastname: Sunnarborg
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: David
authors.initials: D
authors.lastname: Lee
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry*; D000072198:ADAM17 Protein; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D019921:Biotinylation; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D019041:L-Selectin / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D019041:L-Selectin; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D001241:Aspirin