Cardioprotective role of sphingosine-1-phosphate.

Sphingosine-1-phosphate (S1P) has been shown to exert potent cardioprotective action. It binds to the plasma membrane receptors. Three S1P receptors are present in the heart: 1, 2 and 3. Exogenous S1P increases viability of cardiomyocytes incubated under hypoxic conditions. It also reduces the infarct size in isolated, perfused rat heart after ischemia/reperfusion. Formation of S1P in the heart is catalyzed by the enzyme sphingosine kinase 1 and its catabolism by the enzyme sphingosine1-phosphate lyase. Reduction in the activity of sphingosine kinase 1 or knocking out its gene eliminates cardioprotective effect of ischemic preconditioning in mice. Knocking out the sphingosine-1-phosphate lyase gene exerts potent cardioprotective effect against ischemia/reperfusion in the mouse heart. The following mechanism of cardioprotection by S1P is suggested: S1P binds to its membrane receptors and the complex activates protein G. Activated protein G activates PI3K which in turn activates pro-survival Akt kinase. S1P activates also Stat3, a powerful cardioprotectant. It should be added that ischemia/reperfusion increases markedly the myocardial content of two other sphingolipids, namely sphingosine and ceramide. Sphingosine, a direct precursor of S1P, in a high dose is cardiotoxic. Ceramide (the key sphingolipid, a precursor of sphingosine) is claimed to be responsible for activation of apoptosis during ischemia/reperfusion. Therefore, the two latter sphingolipids may counteract, to a certain degree, the cardioprotective action of S1P. It is suggested, that development of specific S1P agonists and compounds modifying activity of the two enzymes could provide important therapeutic tools in the treatment of the heart infarct.