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J. Biol. Chem., Vol. 280, Issue 48, 39716-39722, December 2, 2005

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Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)^*

Barsom Aktas, Miroslava Pozgajova, Wolfgang Bergmeier, Susan Sunnarborg¶, Stefan Offermanns||, David Lee¶, Denisa D. Wagner, and Bernhard Nieswandt1

From the Rudolf Virchow Center for Experimental Biomedicine, Versbacherstrasse 9, 97078 Würzburg, Germany, The Center For Blood Research, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Department of Biochemistry & Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7260, and the ^||Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany

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 GPIb 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 GPIb 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 GPIb 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 GPIb and GPV by an ADAM17-dependent mechanism and that this process can occur in vivo.

Received for publication, July 18, 2005 Accepted for publication September 20, 2005.

^* This work was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant Ni 5564-3 to B. N.) and the Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 49-931-201-48996; Fax: 49-931-201-48123; E-mail: bernhard.nieswandt{at}virchow.uni-wuerzburg.de.

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