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Rescue of Sphingosine Kinase‐1‐knockout Phenotype by 2‐Acetyl‐5‐tetrahydroxybutyl Imidazole (THI) Following Murine Cardiac Arrest is Linked to Changes in Sphingosine‐1‐phosphate and Behenoylceramide Levels
Author(s) -
Berdyshev Evgeny V.,
Gorshkova Irina A.,
Natarajan Viswanathan,
Wang Huashan,
Beiser David G.,
Vanden Hoek Terry L.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.813.17
Subject(s) - sphingosine , ceramide , sphingolipid , sphingosine kinase 1 , sphingosine kinase , sphingosine 1 phosphate , lipid signaling , ceramide synthase , knockout mouse , endocrinology , medicine , kinase , biology , microbiology and biotechnology , chemistry , receptor , biochemistry , apoptosis
Sphigosine‐1‐phosphate (S1P) signaling system is well documented to be critical for the resistance to different stress conditions. Both sphingosine kinase 1 (SphK1) and S1P lyase (S1PL) are crucial for maintaining S1P levels and regulating entire sphingolipid metabolism. Using our model of cardiac arrest and return of spontaneous circulation we tested the association of rescue of SphK1‐knockout poor survival after cardiac arrest by THI, an inhibitor of S1PL, with changes in S1P and ceramide levels. The LC/MS/MS analysis of circulating and cardiac S1P and ceramide content revealed a decrease in circulating and cardiac S1P levels in SphK1‐KO mice but also a unique association between the lack of SphK1 and changes in tissue and plasma N‐behenoylceramide (C22:0) content. The inhibition of S1PL in SphK1‐KO mice completely reversed poor animal survival after cardiac arrest, which was accompanied by a full reversal of dysregulated S1P and ceramide phenotype caused by the lack of SphK1. The SphK1‐KO phenotype and its reversal by S1PL inhibition were also characterized by dynamic changes in the expression of S1P receptors 1 and 2. Our data demonstrate the link between the lack of SphK1 and particular dysregulation in S1P and ceramide homeostasis which becomes critical for animal survival after cardiac arrest and can be reversed through S1PL inhibition.