title: Interplay between SAFE and RISK pathways in sphingosine-1-phosphate-induced cardioprotection.
abstract: OBJECTIVE
  We studied the role of two powerful molecular signalling mechanisms involved in the cardioprotective effect of sphingosine-1-phosphate (S1P), a major component of high density lipoprotein (HDL) against myocardial ischaemic-reperfusion injury, namely the RISK pathway (Akt/Erk), including its downstream target FOXO-1 and, the SAFE pathway (TNF/STAT-3).
  
  
  METHODS
  Control hearts from wildtype, TNF deficient (TNF(-/-)) or cardiomyocyte STAT-3 deficient (STAT-3(-/-)) male mice were perfused on a Langendorff apparatus (35 min global ischaemia and 45 min reperfusion). S1P (10 nM) was given at the onset of reperfusion for the first 7 min, with/without STAT-3 or Akt inhibitors, AG490 and wortmannin (W), respectively.
  
  
  RESULTS
  S1P reduced myocardial infarct size in wildtype hearts (39.3±4.4% in control vs 17.3±3.1% in S1P-treated hearts; n≥6; p<0.05) but not in STAT-3(-/-) or TNF(-/-) mice (34.2±4.3% in STAT-3(-/-) and 34.1±2.0% in TNF(-/-) mice; n≥6; p=ns vs. their respective control). Both STAT-3 and Akt inhibitors abolished the protective effects of S1P (33.7±3.3% in S1P + AG490 and 36.6±4.9% in S1P + W; n=6; p=ns vs. their respective control). Increased nuclear levels of phosphorylated STAT-3 (pSTAT-3), Akt and FOXO-1 were observed at 15 min reperfusion in wildtype mice with Western Blot analysis (53% STAT-3, 47% Akt, 41% FOXO-1; p<0.05 vs control) but not in STAT-3-/- mice or in wiltype hearts treated with the Akt inhibitor. Interestingly, an activation of pSTAT-3 was noticed in the mitochondria at 7 min but not 15 min of reperfusion.
  
  
  CONCLUSIONS
  In conclusion, S1P activates both the SAFE and RISK pathways, therefore suggesting a dual protective signalling in S1P-induced cardioprotection.
authors.affiliation: Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. sarin54@gmail.com
authors.forename: Sarin J
authors.initials: SJ
authors.lastname: Somers
authors.forename: Miguel
authors.initials: M
authors.lastname: Frias
authors.forename: Lydia
authors.initials: L
authors.lastname: Lacerda
authors.forename: Lionel H
authors.initials: LH
authors.lastname: Opie
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008246:Lysophospholipids; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine