Sphingosine kinase and sphingosine 1-phosphate in cardioprotection

Abstract

Activation of sphingosine kinase/sphingosine 1-phosphate-mediated signaling has emerged as a critical cardioprotective pathway in response to acute ischemia/reperfusion injury. Application of exogenous sphingosine 1-phosphate (S1P) in cultured cardiac myocytes subjected to hypoxia or treatment of isolated hearts either before ischemia or at the onset of reperfusion (pharmacologic preconditioning or postconditioning) exerts prosurvival effects. Synthetic congeners of S1P mimic these responses. Gene-targeted mice null for the sphingosine kinase 1 isoform whose hearts are subjected to ischemia/reperfusion injury exhibit increased infarct size and respond poorly either to ischemic preconditioning or to ischemic postconditioning. Measurements of cardiac sphingosine kinase activity and S1P parallel these observations. High-density lipoprotein is a major carrier of S1P, and studies of hearts in which selected S1P receptors have been deleted implicate the S1P cargo of high-density lipoprotein in cardioprotection. These observations have considerable relevance for future therapeutic approaches to acute and chronic myocardial injury.

FIGURE 1

Regulation and function of SK1. The diagram depicts some of the negative and positive regulators of SK1 activity and the synthesis and location of the SK1/S1P pathway either present in the heart or derived experimentally. A key feature of this pathway is the conversion of the ubiquitous membrane lipid sphingomyelin by several sphingomyelinases manufactured intracellularly that act both at the membrane level and extracellularly. This results in the generation of ceramide that is deacylated by neutral ceramidase, yielding sphingosine, which is then converted to S1P by the action of SK1. As noted in the text, activation of SK1 in the heart is inhibited by I/R injury and is stimulated by monoganglioside GM-1 that like IPC requires activation of PKCε. SK1 activity can also be influenced negatively or positively by the interacting proteins shown and by many other agonists described in the text. As shown in the figure, SK1 generates intracellular S1P that may act in as yet poorly defined ways on mitochondria, nuclei, or other targets. Intracellular S1P is known to be exported (“inside-out signaling”) to act as an autocrine or paracrine messenger via G-protein–coupled cell surface receptors. A second isoform of SK (SK2) is also responsible for S1P generation (not shown). The location of S1P generation within the cell may determine its effect, but the outcomes of such location-based effects have not been determined. As shown in the figure, S1P is also generated extracellularly by a sequence of enzyme reactions similar to those described above. I/R, ischemia/reperfusion.