Isoflurane preconditioning decreases myocardial infarction in rabbits via up-regulation of hypoxia inducible factor 1 that is mediated by mammalian target of rapamycin
Isoflurane preconditioning decreases myocardial infarction in rabbits via up-regulation of hypoxia inducible factor 1 that is mediated by mammalian target of rapamycin
复制标题
DOI：
10.1097/aln.0b013e318164cab1
复制
发表时间：
2008-03-01
期刊：
影响因子：
8.8
通讯作者：
Gozal, Yaacov
中科院分区：
文献类型：
--
作者：
Raphael, Jacob;Zuo, Zhiyi;Gozal, Yaacov
背景-挥发性麻醉药已知可保护心脏免受缺血-再灌注损伤。作者测试了异氟醚麻醉预处理是否是通过激活转录因子缺氧诱导因子1（HIF-1）介导的，并评估了哺乳动物雷帕霉素靶信号在此过程中的作用。方法：新西兰白色兔进行40分钟的局部心肌缺血，然后再灌注180分钟，被分配到以下组：仅局部缺血和再灌注（I/R）、异氟烷（I最小肺泡浓度）预处理和在雷帕霉素的哺乳动物靶抑制剂雷帕霉素（0.25 mg/kg）存在下的异氟烷预处理。还包括假手术组、异氟烷+假手术组、雷帕霉素+假手术组、雷帕霉素+ I/R组和二甲亚砜+ I/R组。肌酸激酶MB水平作为心肌损伤的指标进行评估，梗死面积通过氯化三苯基四氮唑染色进行评估。结果：异氟醚预处理组与I/R组相比，心肌梗死面积减少26 ± 4%与44 ± 6%（P < 0.05）。预处理组动物的肌酸激酶MB浓度（高于基线103 +/- 8%）低于I/R组（高于基线243 +/- 12%; P < 0.05）。雷帕霉素抑制了异氟烷的心脏保护作用：心肌梗死增加至44.4%，肌酸激酶MB水平增加至基线水平的254 +/- 9%。与缺血组相比，异氟醚预处理后HIF-1 α蛋白表达和DNA结合活性增加。这些影响也被抑制雷帕霉素。结论：目前的结果表明，异氟烷诱导的心肌保护涉及激活的HIF-1通路介导的哺乳动物靶雷帕霉素。
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 (I 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-1 alpha expression and DNA binding were assessed by Western blotting and electrophoretic mobility shift analysis, respectively.Results: isoflurane preconditioning reduced infarct size com pared 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-1 alpha 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.