This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.This study was supported by the Federal Ministry of Education and Research (BMBF, Germany, FKZ 01EO1502). This work was supported, in part, by the William Harvey Research Foundation and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit that is supported and funded by the National Institute of Health Research. This work also contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences supported by the Barts and The London Charity (Award 753/1722). JP was supported by the German Research Foundation SFB 1039. AH was supported by the Swiss National Science Foundation

Bauer, M

Benetti, E

Coldewey, SM

Collino, M

Huwiler, A

Pfeilschifter, J

Sponholz, C

Thiemermann, C

Scientific Reports

PubMed

Benetti, Elisa

Collino, Massimo

Institutional Research Information System University of Turin

English

Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis

AbstractSerum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.</jats:p

Sina M. Coldewey

Elisa Benetti

Massimo Collino

Josef Pfeilschifter

Christoph Sponholz

Michael Bauer

Andrea Huwiler

Christoph Thiemermann

Crossref

Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720

Coldewey, Sina

Pfeilschifter, Josef

Sponholz, Christoph

Bauer, Michael

Huwiler, Andrea

Thiemermann, Christoph

Hochschulschriftenserver - Universität Frankfurt am Main

Coldewey, Sina M

Bern Open Repository and Information System (BORIS)

Queen Mary Research Online

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/13380/Elevation%20of%20serum%20sphingosine-1-phosphate%20attenuates%20impaired%20cardiac%20function%20in%20experimental%20sepsis.pdf?sequence=1

Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis

Abstract

Similar works

Full text

Available Versions

Institutional Research Information System University of Turin

Crossref

Hochschulschriftenserver - Universität Frankfurt am Main

Bern Open Repository and Information System (BORIS)

Queen Mary Research Online