Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury.
Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury.
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DOI：
10.1161/strokeaha.114.004816
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发表时间：
2014-05
期刊：
影响因子：
8.3
通讯作者：
Iadecola C
中科院分区：
文献类型：
--
作者：
Jackman KA;Zhou P;Faraco G;Peixoto PM;Coleman C;Voss HU;Pickel V;Manfredi G;Iadecola C
阻塞性睡眠呼吸暂停（OSA）是一种与慢性间歇性缺氧（CIH）相关的疾病，会增加中风的风险。然而，CIH已被报道增加或减少局灶性脑缺血模型中的脑损伤。决定CIH对缺血性损伤的不同作用的因素及其机制尚不清楚。在这里，我们测试的假设，缺氧的挑战的强度决定了CIH的保护性或破坏性的性质，通过调节线粒体损伤的阻力。雄性C57 Bl/6 J小鼠暴露于CIH与10%或6%O2长达35天，并进行短暂的大脑中动脉闭塞（MCAO）。3天后评估运动缺陷和梗死体积。采用激光多普勒血流仪测量缺血期CBF，采用动脉自旋标记MRI测量静息期CBF。在离体脑线粒体中评价了Ca 2+诱导的线粒体去极化和活性氧（ROS）产生。我们发现10%CIH具有神经保护作用，而6%CIH则加重组织损伤。在6%和10%CIH之间未观察到静息或缺血内CBF的差异。然而，10%CIH减少，而6%CIH增加线粒体ROS的产生和对Ca 2+诱导的去极化的敏感性。CIH对缺血性脑的影响是二分的，并且可以部分归因于线粒体对损伤的易感性的变化。研究结果强调了CIH对大脑影响的先前未被认识的复杂性，在评估与循环缺氧相关的条件的神经影响时需要考虑这一点。
Obstructive sleep apnea (OSA), a condition associated with chronic intermittent hypoxia (CIH), carries an increased risk of stroke. However, CIH has been reported to either increase or decrease brain injury in models of focal cerebral ischemia. The factors determining the differential effects of CIH on ischemic injury and their mechanisms remain unclear. Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury. Male C57Bl/6J mice were exposed to CIH with 10% or 6% O2 for up to 35 days and subjected to transient middle cerebral artery occlusion (MCAO). Motor deficits and infarct volume were assessed 3 days later. Intra-ischemic CBF was measured by laser-Doppler flowmetry and resting CBF by arterial spin labeling MRI. Ca2+-induced mitochondrial depolarization and reactive oxygen species (ROS) production were evaluated in isolated brain mitochondria. We found that 10% CIH is neuroprotective, while 6% CIH exacerbates tissue damage. No differences in resting or intra-ischemic CBF were observed between 6% and 10% CIH. However, 10% CIH reduced, while 6% CIH increases mitochondrial ROS production and susceptibility to Ca2+-induced depolarizations. The influence of CIH on the ischemic brain is dichotomous and can be attributed in part to changes in the mitochondrial susceptibility to injury. The findings highlight a previously unappreciated complexity in the effect of CIH on the brain, which needs to be considered in evaluating the neurological impact of conditions associated with cyclic hypoxia.