Involvement of Rac in thromboxane a₂-induced human platelet activation: Regulation of sCD40 ligand release and PDGF-AB secretion

We have previously shown that glycoprotein Ib/IX/V activation stimulates the release of the soluble CD40 ligand (sCD40L) via the generation of thromboxane A₂ from human platelets. In the present study, the role of Rac, which is a member of the Rho family, was investigated in the thromboxane A₂-stimulated release of platelet-derived growth factor (PDGF)-AB and sCD40L in human platelets. U46619, a thromboxane receptor agonist, stimulated the activation of Rac time-dependently in human platelets, and NSC23766, a selective inhibitor of the Rac-guanine nucleotide exchange factor interaction, reduced the U46619-induced platelet aggregation. NSC23766 markedly suppressed the U46619-induced p38 mitogen-activated protein (MAP) kinase phosphorylation. The thromboxane A₂-induced release of PDGF-AB and sCD40L was significantly suppressed by NSC23766 in a dose-dependent manner. In addition, NSC23766 reduced the sCD40L release stimulated by ristocetin, a glycoprotein Ib/IX/V activator. These results indicate that Rac regulates the thromboxane A₂-induced stimulation of PDGF-AB secretion and sCD40L release via the p38 MAP kinase in human platelets.