Nitric oxide triggers delayed anesthetic preconditioning-induced cardiac protection via activation of nuclear factor-κB and upregulation of inducible nitric oxide synthase
Nitric oxide triggers delayed anesthetic preconditioning-induced cardiac protection via activation of nuclear factor-κB and upregulation of inducible nitric oxide synthase
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DOI：
10.1097/shk.0b013e31816ad19
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发表时间：
2008-09-01
期刊：
影响因子：
3.1
通讯作者：
Chan, Julie Y. H.
中科院分区：
文献类型：
--
作者：
Chen, Chen Hsiu;Chuang, Jiin Haur;Chan, Julie Y. H.
一氧化氮 (NO) 在麻醉诱导预处理 (APC) 期间触发和介导针对心肌 I/R 损伤的延迟保护方面发挥着关键作用。然而，这种现象背后的信号机制仍不清楚。本研究使用异氟烷作为代表性麻醉剂，检验了这样的假设：麻醉诱导的预处理后释放的 NO 通过激活核转录因子-κ B (NF-κ B) 启动延迟心脏保护，通过 iNOS 上调和 NO 产生增加导致心肌适应。在戊巴比妥麻醉下接受开胸手术的 Sprague-Dawley 大鼠接受 30 分钟的左冠状动脉闭塞，然后再灌注 120 分钟。缺血前 24 小时暴露于 2.1% 异氟醚吸入氧气 60 分钟，可显着减少 I/R 诱导的心肌梗死面积，这与 iNOS 蛋白过度表达和心脏中 NO 含量增加有关。在左冠状动脉闭塞之前，在异氟烷之前使用 NOS 抑制剂 N-G-硝基-L-精氨酸甲酯、NF-κ B 阻滞剂二乙基二硫代氨基甲酸酯或选择性 iNOS 抑制剂 S-甲基异硫脲进行预处理，可以消除这些保护作用。异氟烷暴露还会引起心肌 NO 含量的大幅增加，随后 NF-κ B 的 p65 或 p50 亚基发生核结合易位，并增加心脏组织中 NF-κ B DNA 结合活性。异氟烷暴露后的这些分子事件可通过 N-G-硝基-L-精氨酸甲酯预处理来阻断。我们得出的结论是，异氟醚暴露后立即产生的 NO 会触发下游 NF-kappa B 的激活，导致随后 iNOS 表达和 NO 合成上调，从而介导 APC 诱导的延迟心脏保护。
Nitric oxide (NO) plays a pivotal role both in triggering and mediating delayed protection against myocardial I/R injury during anesthetic-induced preconditioning (APC). However, the signaling mechanisms that underlie this phenomenon remain unclear. Using isoflurane as a representative anesthetic, the present study tested the hypothesis that NO released after anesthetic-induced preconditioning initiates delayed cardioprotection via activation of nuclear transcription factor-kappa B (NF-kappa B), leading to myocardial adaptation by upregulation of iNOS and increase in production of NO. Sprague-Dawley rats that received open-chest surgery under pentobarbital anesthesia were subject to 30 min of left coronary artery occlusion, followed by 120 min of reperfusion. Exposure to 60 min of 2.1% isoflurane inhalation with oxygen 24 h before ischemia significantly reduced I/R-induced myocardial infarct size that was associated with overexpression of iNOS protein and increased NO content in the heart. These protective effects were abolished by pretreatment with a NOS inhibitor, N-G-nitro-L-arginine methyl ester, an NF-kappa B blocker, diethyldithiocarbamate, before isoflurane, or a selective iNOS inhibitor, S-methylisothiourea, before left coronary artery occlusion. Isoflurane exposure also evoked a robust increase in myocardial NO content, followed by nucleus-bound translocation of p65 or p50 subunit of NF-kappa B and increase in NF-kappa B DNA-binding activity in heart tissues. These molecular events after isoflurane exposure were blocked by pretreatment with N-G-nitro-L-arginine methyl ester. We conclude that NO generated immediately after isoflurane exposure triggers downstream activation of NF-kappa B, resulting in subsequent upregulation of iNOS expression and NO synthesis that mediate APC-induced delayed cardioprotection.