Priming of Platelet alphaIIb beta3 by Oxidants Is Associated With Tyrosine Phosphorylation of beta3

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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 H2 O2, a major cellular oxidant. Exposure to H2 O2 triggered platelet aggregation, but only when the platelets were stirred. Strong platelet aggregation induced by H2 O2 required the presence of the tyrosine phosphatase inhibitor sodium orthovanadate (NaVO4) and was dependent on the participation of integrin alphaIIb beta3 (glycoprotein IIb-IIIa). A specific inhibitor of alphaIIb beta3 blocked platelet aggregation induced by H2 O2 and NaVO4, thus confirming that aggregation requires this receptor. In the presence of H2 O2 and NaVO4, multiple platelet substrates were phosphorylated on tyrosine. Such tyrosine kinase response was necessary but not sufficient to activate alphaIIb beta3, as detected by binding of soluble fibrinogen to platelets. Stirring of the platelets exposed to H2 O2 and NaVO4 was also needed to allow for binding of fibrinogen to alphaIIb beta3. The tyrosine kinase inhibitor genistein was able to block platelet aggregation induced by H2 O2 and NaVO4, thus confirming that tyrosine kinase activity was needed to trigger alphaIIb beta3 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 H2 O2 and NaVO4. We found that beta3 was phosphorylated on tyrosine in platelets exposed to H2 O (2) and NaVO4, even in the absence of aggregation. Hence, tyrosine phosphorylation of beta3 might contribute to the "priming" of alphaIIb beta3 induced by H2 O2 and NaVO4, whereby the receptor can become activated on stirring of the platelets. (Arterioscler Thromb Vasc Biol. 1998;18:1698-1706.)

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