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Survival of Sphingosine Kinase‐1 Knockout Phenotype in Cardiac Arrest by the Inhibition of Sphingosine‐1‐Phosphate Lyase
Author(s) -
Berdyshev Evgeny,
Gorshkova Irina,
Goya Jonathan,
Beiser David G.,
Wang Huashan,
Orbelyan Gerasim,
Natarajan Viswanathan,
Vanden Hoek Terry L.
Publication year - 2011
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.25.1_supplement.739.2
Sphingosine‐1‐phosphate (S1P) is an important regulator of pro‐survival signaling. Two sphingosine kinases (SK), SK1 and SK2, form S1P in cells while S1P lyase irreversibly degrades S1P and controls the total pool of cellular sphingolipids. Deletion of the SK1 gene is detrimental in both in vitro and in vivo models of ischemia/reperfusion induced injury. Using our mouse model of cardiac arrest and return of spontaneous circulation (CA/ROSC), we tested the hypothesis that SK1 knockout (SK1‐KO) mice will demonstrate decreased survival after CA/ROSC, and that upregulation of S1P levels via pharmacological S1P lyase inhibition will rescue the effect of SK1 gene deletion in this model. LC/MS/MS analysis of heart tissue and plasma showed significant reductions in S1P levels in SK1‐KO compared to C57Bl/6 mice (p<0.05). SK1‐KO mice demonstrated 50% ROSC but failed to achieve 4 h survival. Inhibition of S1P lyase by tetrahydroxybutylimidazole (THI) almost doubled S1P levels in the heart and in the plasma of SK1‐KO and C57Bl/6 mice compared to non‐treated animals. Importantly, treatment with THI significantly improved the ROSC rate (to 83%) and 4 h survival (to 66%) of SK1‐KO mice. S1P lyase inhibition was accompanied by the upregulation of Bcl‐2 protein expression. Our data demonstrate the importance of SK1‐S1P axle in determining survival during cardiac arrest.