title: Isoflurane preconditioning decreases myocardial infarction in rabbits via up-regulation of hypoxia inducible factor 1 that is mediated by mammalian target of rapamycin.
abstract: BACKGROUND
  Volatile anesthetics are known to protect the heart against ischemia-reperfusion injury. The authors tested whether anesthetic preconditioning with isoflurane is mediated via activation of the transcription factor hypoxia inducible factor 1 (HIF-1) and evaluated the role of mammalian target of rapamycin signaling in this process.
  
  
  METHODS
  New Zealand White rabbits subjected to 40 min of regional myocardial ischemia, followed by 180 min of reperfusion, were assigned to the following groups: ischemia and reperfusion (I/R) only, isoflurane (1 minimal alveolar concentration) preconditioning, and isoflurane preconditioning in the presence of the mammalian target of rapamycin inhibitor rapamycin (0.25 mg/kg). Sham-operated, isoflurane + sham, rapamycin + sham, rapamycin + I/R, and dimethyl sulfoxide + I/R groups were also included. Creatine kinase-MB levels were assessed as an indicator of myocardial damage, and infarct size was evaluated by triphenyl tetrazolium chloride staining. HIF-1alpha expression and DNA binding were assessed by Western blotting and electrophoretic mobility shift analysis, respectively.
  
  
  RESULTS
  Isoflurane preconditioning reduced infarct size compared with the I/R group: 26 +/- 4% versus 44 +/- 6% (P < 0.05). Creatine kinase-MB concentrations in the preconditioned animals (103 +/- 8% above baseline) were lower than in the I/R group (243 +/- 12% above baseline; P < 0.05). Rapamycin inhibited the cardioprotective effect of isoflurane: myocardial infarction increased to 44 +/- 4% and creatine kinase-MB level increased to 254 +/- 9% above baseline. HIF-1alpha protein expression and DNA binding activity increased after isoflurane preconditioning compared with the ischemia group. These effects were also inhibited by rapamycin.
  
  
  CONCLUSIONS
  The current results indicate that isoflurane-induced myocardial protection involves activation of the HIF-1 pathway that is mediated by the mammalian target of rapamycin.
authors.affiliation: Department of Anesthesiology, University of Virginia Health Sciences System, Charlottesville, Virginia 22908, USA. jr5ef@virginia.edu
authors.forename: Jacob
authors.initials: J
authors.lastname: Raphael
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
authors.forename: Suzan
authors.initials: S
authors.lastname: Abedat
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Gozal
mesh_terms: D000818:Animals; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000517:prevention & control; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D007530:Isoflurane; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases