Direct evidence for inhibition of mitochondrial permeability transition pore opening by sevoflurane preconditioning in cardiomyocytes: Comparison with cyclosporine A
Direct evidence for inhibition of mitochondrial permeability transition pore opening by sevoflurane preconditioning in cardiomyocytes: Comparison with cyclosporine A
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DOI：
10.1016/j.ejphar.2011.11.040
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发表时间：
2012-01-30
影响因子：
5
通讯作者：
Figueredo, Vincent M.
中科院分区：
文献类型：
--
作者：
Onishi, Anna;Miyamae, Masami;Figueredo, Vincent M.
为了评估七氟烷预处理是否与线粒体通透性转换孔（MPTP）抑制相关，将七氟烷的作用与环孢霉素A（一种已知的MPTP开放抑制剂）的作用进行了比较。豚鼠离体心脏缺血30 min，再灌注120 min（对照组）。七氟醚预处理是通过在缺血前给予2%七氟醚10 min和10 min洗脱（七氟醚）来引起的。一个预处理样的心脏保护也诱导给予环孢素A（0.2 μ M）15分钟，缺血前5分钟开始，再灌注（环孢素A）开始后10分钟。测量左室舒张末期压、冠状动脉血流量和梗死面积。通过蛋白质印迹分析测定Akt和糖原合成酶激酶3 β（GSK 3 β）（已知抑制MPTP开放的介质）的表达。用LY294002实现GSK 3 β抑制。评估了七氟烷和环孢素A对钙诱导的MPTP开放的影响。缺血再灌注后，七氟醚和环孢素A具有较高的左室发展压。与对照组相比，七氟烷和环孢素A组的颅内压大小显著降低。在七氟烷中，LY294002可消除该效应，但在环孢素A中未消除。七氟烷和环孢霉素A组再灌注后Akt和GSK3 β磷酸化显著增加。在七氟烷和环孢素A中，Ca2+诱导的钙黄绿素荧光降低显著减弱。预处理剂，七氟烷和环孢素A增加钙诱导的MPTP开放的阈值到类似的程度。七氟烷而非环孢素A的这种作用至少部分由GSK 3 β失活介导。(C)2011 Elsevier B.V.保留所有权利。
To assess whether sevoflurane preconditioning is associated with inhibition of mitochondrial permeability transition pore (MPTP), the effects of sevoflurane were compared with those of cyclosporine A, a known inhibitor of MPTP opening. Isolated perfused guinea pig hearts underwent 30 min global ischemia and 120 min reperfusion (control). Sevoflurane preconditioning was elicited by administration of 2% sevoflurane for 10 min with 10 min washout before ischemia (sevoflurane). A preconditioning-like cardioprotection was also induced by administering cyclosporine A (0.2 mu M) for 15 min, starting 5 min before ischemia and for 10 min after the onset of reperfusion (cyclosporine A). Left ventricular developed and end-diastolic pressures, coronary flow and infarct size were measured. Expressions of Akt and glycogen synthase kinase 3 beta (GSK3 beta), known mediators of inhibition of MPTP opening, were determined by Western blot analysis. GSK3 beta inhibition was achieved with LY294002. The effects of sevoflurane and cyclosporine A on calcium-induced MPTP opening in isolated calcein-loaded mitochondria were assessed. After ischemia-reperfusion, sevoflurane and cyclosporine A had higher left ventricular developed pressure. Infarct size was significantly reduced in sevoflurane and cyclosporine A vs. control. This was abolished by LY294002 in sevoflurane, but not in cyclosporine A. Akt and GSK3 beta phosphorylation after reperfusion were significantly increased in sevoflurane and cyclosporine A. Ca2+-induced reduction in calcein fluorescence was significantly attenuated in sevoflurane and cyclosporine A. Preconditioning agents, sevoflurane and cyclosporine A increase the threshold of calcium-induced MPTP opening to a similar extent. This effect by sevoflurane, but not cyclosporine A is at least partially mediated by GSK3 beta inactivation. (C) 2011 Elsevier B.V. All rights reserved.