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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1698-1706.)
© 1998 American Heart Association, Inc.

Original Contributions

Priming of Platelet _IIbß₃ by Oxidants Is Associated With Tyrosine Phosphorylation of ß₃

Kaikobad Irani; Youm Pham; Lindsay D. Coleman; Christine Roos; Glen E. Cooke; Amir Miodovnik; Nayeem Karim; Calvin C. Wilhide; Paul F. Bray; ; Pascal J. Goldschmidt-Clermont

From the Division of Cardiology, Department of Medicine (K.I., N.K., C.C.W.) and the Division of Hematology, Departments of Medicine and Pathology (L.D.C., P.F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; and the Heart and Lung Institute and Cardiology Division, Department of Medicine (Y.P., C.R., G.E.C., A.M., P.J.G.-C.), Ohio State University, Columbus.

Correspondence to Pascal J. Goldschmidt-Clermont, Heart and Lung Institute, Medical Research Facility, Suite 514, Ohio State University, 420 W 12th St, Columbus, OH 43210. E-mail Goldschmidt-1{at}medctr.osu.edu

Abstract—Reactive oxygen species play an important role at the site of vascular injuries and arterial thromboses. We studied the mechanism mediating platelet aggregation induced by H₂O₂, a major cellular oxidant. Exposure to H₂O₂ triggered platelet aggregation, but only when the platelets were stirred. Strong platelet aggregation induced by H₂O₂ required the presence of the tyrosine phosphatase inhibitor sodium orthovanadate (NaVO₄) and was dependent on the participation of integrin _IIbß₃ (glycoprotein IIb-IIIa). A specific inhibitor of _IIbß₃ blocked platelet aggregation induced by H₂O₂ and NaVO₄, thus confirming that aggregation requires this receptor. In the presence of H₂O₂ and NaVO₄, multiple platelet substrates were phosphorylated on tyrosine. Such tyrosine kinase response was necessary but not sufficient to activate _IIbß₃, as detected by binding of soluble fibrinogen to platelets. Stirring of the platelets exposed to H₂O₂ and NaVO₄ was also needed to allow for binding of fibrinogen to _IIbß₃. The tyrosine kinase inhibitor genistein was able to block platelet aggregation induced by H₂O₂ and NaVO₄, thus confirming that tyrosine kinase activity was needed to trigger _IIbß₃ activation on stirring. N-Acetyl-L-cysteine, a cell-permeant antioxidant, blocked the tyrosine phosphorylation of platelet substrates and also the platelet aggregation induced by H₂O₂ and NaVO₄. We found that ß₃ was phosphorylated on tyrosine in platelets exposed to H₂O₂ and NaVO₄, even in the absence of aggregation. Hence, tyrosine phosphorylation of ß₃ might contribute to the "priming" of _IIbß₃ induced by H₂O₂ and NaVO₄, whereby the receptor can become activated on stirring of the platelets.

Key Words: reactive oxygen species • platelets • tyrosine kinases • glycoprotein IIb-IIIa • shear

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