The main findings of this study are: (I) activated platelets release S1P during AMI through the S1P exporter Mfsd2b; (II) platelet-derived S1P during AMI is cardioprotective by engaging the cardiomyocyte S1P1; (III) platelet S1P-mediated cardioprotection is preserved with GPIIb/IIIa antagonists, but not P2Y12 antagonists and (IV) higher plasma S1P concentrations in STEMI patients at admission are favorably associated with infarct size and cardiovascular mortality during 12 months follow-up (Fig. 4). The gene discussed is S1PR1; the disease is infarction.