Upon activation, platelets release various mediators, which not only act as enhancers of platelet activation, but exert proinflammatory effect in the vessel wall. One of these molecules is sphingosine-1-phosphate (S1P). S1P is a sphingosine-derived lipid signaling molecule of key importance for the vascular homeostasis and is stored in large quantities in platelets. Platelet-derived S1P has been suggested as major regulator of endothelial cell (EC) growth and migration. Recent data from our laboratory indicate that its release from human platelets is dependent on the formation of thromboxane (TX) and subsequent activation the TX receptor. Consequently, secretion of S1P is inhibited by acetylsalicylic acid (aspirin) and by other inhibitors of cyclooxygenase-1. This was determined in vitro and was also evident after oral intake of aspirin (100 mg once daily over three days or 500 mg single dose) in healthy volunteers. Interestingly, S1P release was independent of platelet granule secretion. The underlying mechanism appears to involve activation of the protein kinase C and a final export of S1P by members of the ABC transporter family. In subsequent studies, we observed that the administration of aspirin attenuates the release of S1P also in patients with acute coronary syndrome. This indicates the potential relevance of platelet-derived S1P in clinical conditions of enhanced platelet activation. Further data indicate the role of platelet-derived S1P for EC and monocyte migration, key features of inflammatory processes in the vessel wall. While S1P did not appear to exert a major influence on the activation of platelets in vitro, platelet-derived S1P stimulated EC migration and modulated the chemotactic capacity of human monocytes after long term incubation. Selective inhibitors and transcriptional downregulation by RNA interference indicated that these paracrine effects of platelet-derived S1P were mediated via the S1P receptor-1 in EC and via S1P receptors-1 and -3 in monocytes.

Our data suggest that the release of S1P from activated human platelets depends on the formation of endogenous thromboxane. The biological effects of platelet-derived S1P involve EC and monocyte activation rather than autocrine functions. S1P release from platelets under conditions of enhanced thrombin formation and platelet activation may be an attractive future pharmacological target to interfere with proinflammatory paracrine platelet functions.