Involvement of the glycoproteic Ib-V-IX complex in nickel-induced platelet activation

We studied the effect of nickel ions on platelet function because hypernickelemia has been found in patients with acute myocardial infarction. We previously demonstrated that nickel can activate an intracellular pathway leading to cytoskeleton reorganization consequent to tyrosine phosphorylation of p60(src) in human platelets independently of integrin alpha-IIb-beta(3) (alpha IIb beta3). Moreover, in von Willebrand factor-stimulated platelets, the tyrosine phosphorylation of pp60(c-src) is closely associated with the activation of phosphatidylinositol S-kinase (PIK), and two adhesion receptors, glycoprotein (Gp)Ib and GpIIb/IIIa (alpha IIb beta3), are involved. In our study, 1 and 5 mM nickel in the presence of fibrinogen induced platelet aggregation (independently of protein kinase C activation) and secretion. The pretreatment with a PIK inhibitor, wortmannin, strongly decreased nickel-induced platelet aggregation. Platelet treatment with mocarhagin, a cobra venom metalloprotrinase that cleaves GpIba, significantly reduced aggregation induced by 5 mM without affecting the response to other agonists such as adenosine diphosphate (ADP). Moreover, nickel caused PIK translocation to the cytoskeleton. Taken together, these observations suggest a partial involvement of both integrins alpha IIb beta3 and GpIb-V-IX complex in Ni2+-induced platelet activation.