Isoflurane Preconditioning Decreases Myocardial Infarction in Rabbits via Up-regulation of Hypoxia Inducible Factor 1 That Is Mediated by Mammalian Target of Rapamycin

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.