The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques

Chemokines are chemotactic cytokines that activate and direct the migration of leukocytes. However, their role in modulating platelet function has not been shown. We studied the direct effect of chemokines on human platelets and found that of the 16 tested only stromal cell- derived factor (SDF)-1 i nduced platelet aggregation, accompanied by a rise in intracellular calcium . Platelets expressed the SDF-1 receptor, CXCR4, and an antibody to CXCR4 a nd pertussis toxin inhibited SDF-1-induced platelet aggregation, confirming that this effect is mediated through CXCR4, a G alpha i-coupled receptor. SDF-1-induced platelet aggregation was also inhibited by wortmannin, LY2940 02, and genistein, suggesting that phosphatidylinositol 3-kinase and tyrosi ne kinase are likely involved in SDF-1-induced platelet aggregation. Becaus e chemokines are produced from multiple vascular cells and atherosclerotic vessels are prone, to develop platelet-rich thrombi, we examined the expres sion of SDF-1 in human atheroma. SDF-1 protein was highly expressed in smoo th muscle cells, endothelial cells, and macrophages in human atheroscleroti c plaques but not in normal vessels. Our studies demonstrate a direct effec t of a chemokine in inducing platelet activation and suggest a role for SDF -1 in the pathogenesis of atherosclerosis and thrombo-occlusive diseases.