title: The second window of desflurane-induced preconditioning is mediated by STAT3: role of Pim-1 kinase.
abstract: BACKGROUND
  Late ischemic preconditioning is mediated via nuclear transcription factor signal transducer and activator of transcription 3 (STAT3). Pim-1 kinase reduces infarct size in cardiomyocytes and is regulated by STAT3. We tested the hypothesis that late desflurane-induced preconditioning (DES-SWOP) is mediated via STAT3 and Pim-1.
  
  
  METHODS
  After institutional approval, pentobarbital-anesthetized male C57BL/6 mice were subjected to 45 min coronary artery occlusion (CAO) and 3 h reperfusion. Control animals received no additional intervention. Desflurane was administered 48 h before CAO either alone or in combination with the janus kinase/STAT3 inhibitor AG-490 (40 μg/g i.p., 20 min before desflurane administration) or the Pim-1 kinase inhibitor II (PIM-Inh.II, 10 μg/g i.p., 15 min before CAO). Infarct size (IS) and area at risk were determined with triphenyltetrazolium chloride and Evans blue, respectively. Additionally, cytosolic and nuclear fractions were separated at two different time points and expression of STAT3, phospho-STAT3(Ser727) , phospho-STAT3(Tyr705) , Pim-1, Bad and phospho-Bad(Ser112) were determined by Western Blot analysis. Data were analyzed with one-way or two-way ANOVA and post hoc Duncan test and are presented as mean ± SEM.
  
  
  RESULTS
  IS was 47 ± 2% (n = 7-8 per group) in control animals (CON). DES-SWOP reduced myocardial infarct size to 23 ± 4%* (*P < 0.05 vs. CON). AG-490 alone did not affect myocardial infarct size (44 ± 7%), but abolished DES-SWOP (44 ± 4%). Blockade of Pim-1 did not affect the protection by DES-SWOP (34 ± 4%*). Desflurane reduced cytosolic content and enhanced nuclear content of phospho-STAT(S) (er727) . After 48 h, desflurane enhanced Pim-1 activity, whereas Pim-1 expression remained unchanged.
  
  
  CONCLUSIONS
  These data suggest that DES-SWOP is mediated by activation and nuclear translocation of STAT3. The impact of Pim-1 in DES-SWOP signaling remains unclear.
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Stumpner
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Tischer-Zeitz
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Lotz
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Umminger
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Neuwirth
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Smul
authors.affiliation: Department of Anesthesia, University of Regensburg, Regensburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Redel
authors.affiliation: Department of Anesthesiology and Critical Care, Hospital of Karlsruhe, Karlsruhe, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kehl
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Roewer
authors.affiliation: Department of Anesthesia and Critical Care Medicine, Mathias-Spital Rheine, Rheine, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lange
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D000077335:Desflurane; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015425:Myocardial Reperfusion; D051573:Proto-Oncogene Proteins c-pim-1 / Q000187:drug effects / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; C494820:Bad protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051025:bcl-Associated Death Protein; D000077335:Desflurane; D007530:Isoflurane; D051573:Proto-Oncogene Proteins c-pim-1