Obligatory role of inducible nitric oxide synthase in ischemic preconditioning
Obligatory role of inducible nitric oxide synthase in ischemic preconditioning
复制标题
DOI：
10.1038/sj.jcbfm.9600058
复制
发表时间：
2005-04-01
影响因子：
6.3
通讯作者：
Iadecola, C
中科院分区：
文献类型：
--
作者：
Cho, S;Park, EM;Iadecola, C
亚致死损伤可以诱导对随后的致死缺血的短暂耐受，这种现象称为缺血预处理（IPC）。在心肌中，诱导型一氧化氮合酶（iNOS或NOS II）产生的一氧化氮在亚致死缺血产生的IPC表达中起关键作用。本研究探讨NOS是否参与脑内IPC。小鼠通过三次1分钟的双侧颈总动脉（BCCA）闭塞，每次5分钟的再灌注，产生缺血预处理。24小时后，小鼠进行大脑中动脉（MCA）闭塞20分钟。用激光多普勒血流仪监测BCCA和MCA闭塞（MCAO）期间的缺血性脑血流。MCAO后3天处死小鼠，用硫氨酸染色切片测定梗死体积。IPC后24h梗死面积明显减少（70%;P < 0.05）。用NOS抑制剂氨基胍（400 mg/kg）处理，可消除ipc诱导的保护作用。此外，IPC不能诱导inos缺失小鼠的缺血耐受。在野生型小鼠中，IPC增加了离体脑线粒体对Ca（2+）介导的去极化的抗性。然而，在iNOS-null小鼠中，IPC未能诱导这种抗性。我们得出结论，NOS是IPC完全表达所必需的，并且这种作用与线粒体对损伤的抵抗力增加有关。因此，inos来源的一氧化氮，除了对缺血性脑损伤晚期的有害作用外，还可以通过信号传导促进缺血耐受性，最终导致线粒体保护。
Sublethal insults can induce a transient tolerance toward subsequent lethal ischemia, a phenomenon termed ischemic preconditioning (IPC). In the myocardium, nitric oxide derived from 'inducible' nitric oxide synthase (iNOS or NOS II) plays a critical role in the expression of IPC produced by sublethal ischemia. Here, we investigated whether NOS is involved in IPC in brain. Ischemic preconditioning was produced in mice by three episodes of 1-min bilateral common carotid artery (BCCA) occlusion, each followed by 5 mins of reperfusion. After 24 h, mice underwent middle cerebral artery (MCA) occlusion for 20 mins. Intraischemic cerebral blood flow was monitored during both in BCCA and MCA occlusion (MCAO) by laser-Doppler flowmetry. Mice were killed 3 days after MCAO, and infarct volume was determined in thionine-stained sections. Infarct volume was significantly reduced 24h after IPC (70%; P < 0.05). Treatment with the NOS inhibitor aminoguanidine (400 mg/kg), abolished the IPC-induced protection. Furthermore, IPC failed to induce ischemic tolerance in iNOS-null mice. In wild-type mice, IPC increased the resistance to Ca (2+) -mediated depolarization in isolated brain mitochondria. However, in iNOS-null mice IPC failed to induce such resistance. We conclude that NOS is required for the full expression of IPC and that such effect is coupled to an increased resistance of mitochondria to injury. Thus, iNOS-derived nitric oxide, in addition to its deleterious effects on the late stages of ischemic brain damage, can also be beneficial by promoting ischemic tolerance through signaling, ultimately resulting in mitochondrial protection.