title: Inhibition of sphingosine-1-phosphate lyase rescues sphingosine kinase-1-knockout phenotype following murine cardiac arrest.
abstract: OBJECTIVE
  To test the role of sphingosine-1-phosphate (S1P) signaling system in the in vivo setting of resuscitation and survival after cardiac arrest.
  
  
  METHODS
  A mouse model of potassium-induced cardiac arrest and resuscitation was used to test the importance of S1P homeostasis in resuscitation and survival. C57BL/6 and sphingosine kinase-1 knockout (SphK1-KO) female mice were arrested for 8 min then subjected to 5 minute CPR with epinephrine bolus given at 90s after the beginning of CPR. Animal survival was monitored for 4h post-resuscitation. Upregulation of tissue and circulatory S1P levels were achieved via inhibition of S1P lyase by 2-acetyl-5-tetrahydroxybutyl imidazole (THI). Plasma and heart tissue S1P and ceramide levels were quantified by targeted ESI-LC/MS/MS.
  
  
  RESULTS
  Lack of SphK1 and low tissue/circulatory S1P levels in SphK1-KO mice led to poor animal resuscitation after cardiac arrest and to impaired survival post-resuscitation. Inhibition of S1P lyase in SphK1-KO mice drastically improved animal resuscitation and survival. Improved resuscitation and survival of THI-treated SphK1-KO mice were better correlated with cardiac dihydro-S1P (DHS1P) than S1P levels. The lack of SphK1 and the inhibition of S1P lyase by THI were accompanied by modulation in cardiac S1PR1 and S1PR2 expression and by selective changes in plasma N-palmitoyl- and N-behenoyl-ceramide levels.
  
  
  CONCLUSIONS
  Our data provide evidence for the crucial role for SphK1 and S1P signaling system in resuscitation and survival after cardiac arrest, which may form the basis for development of novel therapeutic strategy to support resuscitation and long-term survival of cardiac arrest patients.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Gorshkova
authors.forename: Huashan
authors.initials: H
authors.lastname: Wang
authors.forename: Gerasim A
authors.initials: GA
authors.lastname: Orbelyan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goya
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: David G
authors.initials: DG
authors.lastname: Beiser
authors.forename: Terry L
authors.initials: TL
authors.lastname: Vanden Hoek
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D016887:Cardiopulmonary Resuscitation / Q000379:methods; D002518:Ceramides / Q000097:blood; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006323:Heart Arrest / Q000503:physiopathology / Q000628:therapy*; D007093:Imidazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D049349:Receptors, Lysosphingolipid / Q000235:genetics; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D015996:Survival Rate; D053719:Tandem Mass Spectrometry / Q000379:methods; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D002518:Ceramides; D007093:Imidazoles; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C556330:S1pr1 protein, mouse; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; C097760:N-palmitoylsphingosine; C049929:2-acetyl-4(5)-tetrahydroxybutylimidazole; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: Cardiac arrest; Dihydrosphingosine-1-phosphate; S1P lyase; S1P signaling system