title: Insulin and GSK3β-inhibition abrogates the infarct sparing-effect of ischemic postconditioning in ex vivo rat hearts.
abstract: OBJECTIVE
  Pharmacological treatment of reperfusion injury using insulin and GSK3β inhibition has been shown to be cardioprotective, however, their interaction with the endogenous cardioprotective strategy, ischemic postconditioning, is not known.
  
  
  METHODS
  Langendorff perfused ex vivo rat hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion. For the first 15 min of reperfusion hearts received either vehicle (Ctr), insulin (Ins) or a GSK3β inhibitor (SB415286; SB41), with or without interruption of ischemic postconditioning (IPost; 3 × 30 s of global ischemia). In addition, the combination of insulin and SB41 for 15 min was assessed.
  
  
  RESULTS
  Insulin, SB41 or IPost significantly reduced infarct size versus vehicle treated controls (IPost 33.5 ± 3.3%, Ins 33.5 ± 3.4%, SB41 30.5 ± 3.0% vs. Ctr 54.7 ± 6.8%, p < 0.01). Combining insulin and SB415286 did not confer additional cardioprotection compared to the treatments given alone (SB41+ Ins 26.7 ± 3.5%, ns). Conversely, combining either of the pharmacological reperfusion treatments with IPost completely abrogated the cardioprotection afforded by the treatments separately (Ins + IPost 59.5 ± 3.4% vs. Ins 33.5 ± 3.4% and SB41 + IPost 50.2 ± 6.6% vs. SB41 30.5 ± 3.0%, both p < 0.01), and was associated with blunted Akt, GSK3β and STAT3 phosphorylation.
  
  
  CONCLUSIONS
  Pharmacological reperfusion treatment with insulin and SB41 interferes with the cardioprotection afforded by ischemic postconditioning.
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Helgeland
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Wergeland
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Rune M
authors.initials: RM
authors.lastname: Sandøy
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Maren
authors.initials: M
authors.lastname: Askeland
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Aspevik
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Breivik
authors.affiliation: a Department of Biomedicine, Faculty of Medicine and Dentistry , University of Bergen , Norway.|b Faculty of Health Science and Medicine , Norwegian University of Science and Technology (NTNU) , Gjøvik , Norway.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Jonassen
mesh_terms: D000627:Aminophenols / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D057775:Ischemic Postconditioning / Q000379:methods*; D000067268:Isolated Heart Preparation; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D007328:Insulin; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; GSK3β; GSK3β inhibition; Heart; STAT3; insulin; ischemia reperfusion injury; ischemic postconditioning; reperfusion