• S M Coldewey, E Benetti, M Collino, M Bauer, A Huwiler, and C Thiemermann.
• 1Clinic for Anaesthesiology and Intensive Care Medicine, University Hospital Jena, Jena, Germany 2Department of Drug Science and Technology, University of Turin, Turin, Italy 3Center for Sepsis Care and Control, University Hospital Jena, Jena, Germany 4Institute of Pharmacology, University of Bern, Bern, Switzerland 5William Harvey Research Institute, Queen Mary University of London, London, UK.
• Shock. 2015 Oct 1;44 Suppl 2:17.

IntroductionThe role of sphingosine-1-phosphate (S1P) and its receptors (S1PR1-5) in septic cardiomyopathy is not known. The S1P mimetic FTY720-P acts as an agonist on all S1P receptors except S1PR2 and as a functional antagonist on S1PR1.MethodsCardiomyopathy was mimicked by co-administration of lipopolysaccharide (LPS) and peptidoglycan (PepG) in wild-type (WT) and sphingosine kinase 2 deficient mice (SPHK2-/-). At 1 h after LPS/PepG mice received FTY720 alone, or a phosphatidylinositol 3 kinase (PI3K) inhibitor or a S1PR2 antagonist prior to FTY720. 18 h later cardiac function was assessed by echocardiography, serum-S1P was measured by LC/MS/MS and expression of signalling molecules was determined by immunoblot analysis.ResultsCompared to sham, mice subjected to LPS/PepG demonstrated a reduction in ejection fraction (EF) and a decrease of serum-S1P. In SPHK2-/--mice, which have higher endogenous S1P- levels, LPS/PepG-induced reduction of EF was blunted. Treatment with FTY720 attenuated the impaired EF in WT-mice accompanied by increased serum-S1P and increased phosphorylation of AKT and eNOS in heart tissue. Cardioprotective effects of FTY720 were abolished following administration of either a PI3K inhibitor or a S1PR2 antagonist. Similar cardioprotective effects of FTY720 were seen in mice with polymicrobial sepsis.ConclusionWe show here for the first time that the impaired left ventricular systolic contractility caused by LPS/PepG is attenuated by a pharmacological or genetic approach to alter S1P-serum levels. Mechanistically, our results indicate that activation of S1PR2 by increased serum S1P and the subsequent activation of PI3K signalling contribute to the observed cardioprotective effect of FTY720 in experimental sepsis.

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