title: In situ postconditioning with neuregulin-1β is mediated by a PI3K/Akt-dependent pathway.
abstract: BACKGROUND
  The myocardial infarct size can be reduced by pharmacological postconditioning using cardioprotective agents. Neuregulin-1β is a potential candidate, but previous studies in an isolated heart model of ischemia and reperfusion displayed controversial results. An in situ model of ischemia/reperfusion was used to clarify whether the remote application of neuregulin-1β can reduce the reperfusion injury. A second aim was to evaluate, if the effects are specific for reperfused tissue or if this is a general antiapoptotic effect. In addition, the contributing molecular mechanisms were investigated.
  
  
  METHODS
  In an open chest model, mouse hearts were subjected to a regional ischemia (45-minute) using ligature of the left anterior descending artery. Neuregulin-1β (80 ng/kg) was given using an intraperitoneal bolus injection 5 minutes before reopening of the ligature followed by a 30-minute reperfusion.
  
  
  RESULTS
  Remote application of recombinant neuregulin-1β protected the heart from reperfusion injury without influencing hemodynamics. This beneficial effect specifically targets reperfusion injury. In contrast, nonreperfused needle trauma was not reduced by neuregulin-1β when applied remotely. Pharmacological blocking experiments and enzyme activation analysis using Western blot analysis revealed a crucial involvement of the antiapoptotic reperfusion injury salvage kinase cascade. In contrast, contribution of the survivor activating factor enhancement pathways to this early cardioprotection was not observed.
  
  
  CONCLUSIONS
  Remote application of neuregulin-1β protects hearts from early reperfusion injury by activation of the reperfusion injury salvage kinase pathway without relevant effects on intracardiac pressures in myocardial infarction. Besides its potential pharmacological application, neuregulin-1β might act as an endogenously produced mediator in remote postconditioning.
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany. Electronic address: Bernd.Ebner@mailbox.tu-dresden.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Ebner
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Lange
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Hollenbach
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Steinbronn
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Ebner
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Clementine
authors.initials: C
authors.lastname: Fischaleck
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Braun-Dullaeus
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Weinbrenner
authors.affiliation: University of Technology Dresden, Department of Medicine and Cardiology, Heart Center Dresden, University Hospital, Dresden, Germany.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020890:Neuregulin-1; C117467:neuregulin beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt