Abstract
Sphingosine-1-phosphate (S1P) regulates distinct biological functions by binding to S1P receptors S1PR1-5 and is generated by phosphorylation of sphingosine via sphingosine kinases (SPHK) 1 and 2. The S1P mimetic FTY720 acts in its phosphorylated isoform as an unselective agonist on S1PR1 and S1PR3-5 and a selective functional antagonist on S1PR1 ([1]). The role of the S1P-S1PR signalling axis in the pathophysiology of septic cardiomyopathy is not known.
Highlights
Sphingosine-1-phosphate (S1P) regulates distinct biological functions by binding to S1P receptors S1PR1-5 and is generated by phosphorylation of sphingosine via sphingosine kinases (SPHK) 1 and 2
To elucidate the mechanisms underlying the observed effects of FTY720 mice were treated with a selective phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002; 0.3 mg/kg bw i.v,) or a selective S1P2 receptor antagonist (JTE013; 1 mg/kg bw i.v.) prior to FTY720. 18 h after LPS/PepG challenge cardiac function was assessed by echocardiography, serum S1P was measured by liquid chromatography-coupled tandem mass spectrometry and expression of selected signalling molecules was determined by immunoblot analysis
Compared to sham, mice subjected to LPS/PepG demonstrated a significant reduction in EF, indicating impaired left ventricular systolic contractility, as well as a significant decrease of serum S1P
Summary
We investigate whether pharmacological or genetic approaches to alter S1P serum levels may attenuate sepsis-induced cardiac dysfunction in mice
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