dihydrosphingosine-1-phosphate and Reperfusion-Injury

Liver failure due to ischemia and reperfusion (IR) and subsequent acute kidney injury are significant clinical problems. We showed previously that liver IR selectively reduced plasma sphinganine-1-phosphate levels without affecting sphingosine-1-phosphate (S1P) levels. Furthermore, exogenous sphinganine-1-phosphate protected against both liver and kidney injury induced by liver IR. In this study, we elucidated the signaling mechanisms of sphinganine-1-phosphate-mediated renal and hepatic protection. A selective S1P(1) receptor antagonist blocked the hepatic and renal protective effects of sphinganine-1-phosphate, whereas a selective S1P(2) or S1P(3) receptor antagonist was without effect. Moreover, a selective S1P(1) receptor agonist, SEW-2871, provided similar degree of liver and kidney protection compared with sphinganine-1-phosphate. Furthermore, in vivo gene knockdown of S1P(1) receptors with small interfering RNA abolished the hepatic and renal protective effects of sphinganine-1-phosphate. In contrast to sphinganine-1-phosphate, S1P's hepatic protection was enhanced with an S1P(3) receptor antagonist. Inhibition of extracellular signal-regulated kinase, Akt or pertussis toxin-sensitive G-proteins blocked sphinganine-1-phosphate-mediated liver and kidney protection in vivo. Taken together, our results show that sphinganine-1-phosphate provided renal and hepatic protection after liver IR injury in mice through selective activation of S1P(1) receptors and pertussis toxin-sensitive G-proteins with subsequent activation of ERK and Akt.

Topics: Acute Kidney Injury; Animals; Extracellular Signal-Regulated MAP Kinases; Ischemia; Kidney; Liver; Liver Diseases; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Oxadiazoles; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; Reperfusion Injury; Signal Transduction; Sphingosine; Thiophenes

The sphingolipid sphingosine-1-phosphate (S1P) plays an important role in protecting the heart against ischemia-reperfusion injury. S1P is normally present in human plasma. However, there are no data available on the effect of myocardial infarction on the plasma concentrations of S1P and related sphingolipids. The aim of this study was to examine the concentrations of S1P, sphinganine-1-phosphate, free sphingosine, free sphinganine, and ceramide in the plasma of patients after myocardial infarction.. The study was performed on two groups of male subjects: controls with no specific complaints (n=21) and patients who had had acute myocardial infarction (n=22). In the latter group, blood was taken immediately after admission to the hospital and five days later. The concentrations of the above compounds were measured by high-pressure liquid chromatography.. The concentrations of S1P and sphinganine-1-phosphate were reduced by ca. 50% both early after infarction and five days later. The concentrations of the other compounds were not affected by myocardial infarction.. The reduction in plasma concentration of S1P after infarction could lessen its protective action on cardiomyocyte viability. The observed reduction in S1P level might be associated with the standard antiplatelet treatment given to patients since thrombocytes are one of the major sources of plasma S1P.

Topics: Aged; Animals; Ceramides; Humans; Lysophospholipids; Male; Mice; Middle Aged; Myocardial Infarction; Myocytes, Cardiac; Receptors, Lysosphingolipid; Reperfusion Injury; Sphingosine; Thrombolytic Therapy