Sevoflurane confers additive cardioprotection to ethanol preconditioning associated with enhanced phosphorylation of glycogen synthase kinase-3β and inhibition of mitochondrial permeability transition pore opening.
Sevoflurane confers additive cardioprotection to ethanol preconditioning associated with enhanced phosphorylation of glycogen synthase kinase-3β and inhibition of mitochondrial permeability transition pore opening.
复制标题
DOI：
10.1053/j.jvca.2012.10.002
复制
发表时间：
2013-10
影响因子：
2.8
通讯作者：
Anna Onishi;M. Miyamae;Hiroshi Inoue;K. Kaneda;C. Okusa;Y. Inamura;Mayumi Shiomi;Shizuka Koshinuma;Y. Momota;V. Figueredo
中科院分区：
文献类型：
--
作者：
Anna Onishi;M. Miyamae;Hiroshi Inoue;K. Kaneda;C. Okusa;Y. Inamura;Mayumi Shiomi;Shizuka Koshinuma;Y. Momota;V. Figueredo
目的探讨七氟烷(SEVO)对中剂量乙醇预适应的保护作用及其与糖原合成酶β(β)、蛋白激酶B(AKT)、雷帕霉素靶标(MTOR)、70 kDa核糖体S6激酶1(P70S6K)和/或线粒体通透性转换孔(MPTP)开放的关系。设计采用离体心朗宁多夫制剂进行体外研究。设置大学研究实验室。对象雄性豚鼠(n=170)。干预：离体豚鼠心脏缺血30分钟，再灌流120分钟(对照组)。乙醇组饮水中加入5%乙醇，连续8周。麻醉预适应是在Etoh(Etoh+Sevo组)或非Etoh(Sevo组)心脏中暴露于2%Sevo 10分钟。分别用LY294002和雷帕霉素抑制β的磷酸化和mTOR。免疫印迹法检测GSK-3β、Akt、mTOR和p70S6K的表达。钙诱导的MPTP开放在分离的钙黄素负载的线粒体中被评估。缺血再灌注后的测量和主要结果：EtoH组、SEVO组和EtoH+SEVO组较对照组有更高的左心室发展压恢复和更低的舒张末压力。与对照组相比，乙醇组和乙醇组的梗塞面积较小，乙醇组和乙醇组的梗塞面积更小。乙醇和SEVO组GSK-3β和Akt的磷酸化水平增加，而mTOR和p70S6K的磷酸化水平无明显变化。乙醇+SEVO组GSK-3mTOR和p70S6Kβ的磷酸化水平进一步升高，而mTOR和p70S6K的磷酸化水平无明显变化。Etoh组和Sevo组钙诱导的MPTP开放较小，Etoh+Sevo组的MPTP开放更小。结论SEVO和慢性无水乙醇预适应具有额外的心脏保护作用。这种作用与GSK-3β磷酸化增加和MPTP开放抑制有关。
OBJECTIVE The purposes of this study were to investigate whether sevoflurane (SEVO) enhances moderate-dose ethanol (EtOH) preconditioning and whether this additional cardioprotection is associated with glycogen synthase kinase-3β (GSK-3β), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 70-kDa ribosomal s6 kinase-1 (p70s6K), and/or mitochondrial permeability transition pore (MPTP) opening. DESIGN In vitro study using an isolated heart Langendorff preparation. SETTING University research laboratory. PARTICIPANTS Male guinea pigs (n = 170). INTERVENTIONS Isolated perfused guinea pig hearts underwent 30-minute ischemia and 120-minute reperfusion (control). The EtOH group received 5% EtOH in the drinking water for 8 weeks. Anesthetic preconditioning was elicited by a 10-minute exposure to 2% SEVO in EtOH (EtOH + SEVO group) or non-EtOH (SEVO group) hearts. The inhibition of GSK-3β phosphorylation and mTOR was achieved with LY294002 and rapamycin, respectively. GSK-3β, Akt, mTOR, and p70s6K expressions were determined by western blot. Calcium-induced MPTP opening was assessed in isolated calcein-loaded mitochondria. MEASUREMENTS AND MAIN RESULTS After ischemia-reperfusion, the EtOH, SEVO, and EtOH + SEVO groups had higher left ventricular developed pressure recovery and lower end-diastolic pressure versus the control group. Infarct size was smaller in the EtOH and SEVO groups versus control and even smaller in the EtOH + SEVO group. Phosphorylation of GSK-3β and Akt, but not mTOR and p70s6K, was increased in the EtOH and SEVO groups. Phosphorylation of GSK-3β, but not mTOR and p70s6K, was further increased in the EtOH + SEVO group. The EtOH and SEVO groups exhibited a smaller calcium-induced MPTP opening, and the EtOH + SEVO presented an even smaller MPTP opening. CONCLUSIONS SEVO and chronic EtOH preconditioning offer additive cardioprotection. This effect is associated with an increased GSK-3β phosphorylation and an inhibition of MPTP opening.