Bauer, M.

Benetti, Elisa

Coldewey, Sm

Collino, Massimo

Huwiler, A.

Thiemermann, C.

English

Institutional Research Information System University of Turin

Enhanced sphingosine-1-phosphate levels by pharmacological or genetic approaches attenuate cardiac dysfunction in experimental septic cardiomyopathy  SM Coldewey, E Benetti, M Collino, M Bauer, A Huwiler, C Thiemermann. Introduction: The 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 S1PR1 and S1PR3-5 and a functional antagonist on S1PR1.  Methods: Cardiomyopathy was mimicked by co-administration of the bacterial cell-wall components lipopolysaccharide (LPS) and peptidoglycan (PepG) in wild-type (WT) and sphingosine kinase 2 deficient mice (SPHK2-/-). At 1h after LPS/PepG mice received FTY720 alone, or they received a phosphatidylinositol 3 kinase (PI3K) inhibitor or a S1P2 receptor antagonist prior to FTY720. 18h 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.  Results: Compared to sham, mice subjected to LPS/PepG demonstrated a reduction in ejection fraction (EF) as well as a decrease of serum-S1P. In SPHK2-/--mice, which have higher endogenous S1P-levels, LPS/PepG-induced reduction of EF was lower than in WT-mice. Treatment with FTY720 attenuated the impaired EF in WT-mice accompanied by an increase of serum-S1P and an increased phosphorylation of AKT and eNOS in heart tissue. Cardioprotective effects of FTY720 were abolished following co-administration of either a PI3K inhibitor or a S1PR2 antagonist. Conclusion: We 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. 

Enhanced sphingosine-1-phosphate levels by pharmacological or genetic approaches attenuate cardiac dysfunction in experimental septic cardiomyopathy

https://iris.unito.it/bitstream/2318/1563299/1/Abstract%202015%20COLDWEY.pdf

Enhanced sphingosine-1-phosphate levels by pharmacological or genetic approaches attenuate cardiac dysfunction in experimental septic cardiomyopathy

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