Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury
Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury
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DOI：
10.1038/s41598-019-50073-8
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发表时间：
2019-09-18
影响因子：
4.6
通讯作者：
Seko, Yoshinori
中科院分区：
文献类型：
--
作者：
Kishimoto, Masao;Suenaga, Jun;Seko, Yoshinori
氧化应激在多种疾病的发病机制中起着重要作用，尤其是在缺血/再灌注（I/R）损伤中。我们鉴定了一种诱导凋亡的体液因子，并将这种新的真核翻译起始因子5A（eIF 5A）的后修饰分泌形式命名为“氧化应激反应性凋亡诱导蛋白”（ORAIP）。本研究旨在探讨ORAIP在脑I/R损伤机制中的作用。缺氧/复氧诱导培养的大鼠脑神经元表达ORAIP，导致这些细胞广泛凋亡，在很大程度上被体外中和性抗ORAIP单克隆抗体（mAb）所抑制。药物ORAIP诱导脑神经元广泛凋亡。脑缺血/再灌注诱导大鼠体内串联闭塞模型中许多神经元表达ORAIP。此外，我们分析了脑室内给予中和性抗ORAIP mAb对脑梗死发生的影响。脑I/R显著增加脑脊液中的ORAIP水平。脑室内给予中和性抗ORAIP mAb治疗可使梗死体积减少72%，即使在再灌注后开始也可减少55%。这些数据有力地表明，ORAIP发挥了关键作用，并将提供一个关键的治疗靶点，脑I/R损伤的溶栓和血栓切除术急性缺血性卒中。
Oxidative stress is known to play a critical role in the pathogenesis of various disorders, especially in ischemia/reperfusion (I/R) injury. We identified an apoptosis-inducing humoral factor and named this novel post translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) "oxidative stress-responsive apoptosis inducing protein" (ORAIP). The purpose of this study was to investigate the role of ORAIP in the mechanisms of cerebral I/R injury. Hypoxia/reoxygenation induced expression of ORAIP in cultured rat cerebral neurons, resulting in extensive apoptosis of these cells, which was largely suppressed by neutralizing anti-ORAIP monoclonal antibody (mAb) in vitro. Recombinant-ORAIP induced extensive apoptosis of cerebral neurons. Cerebral I/R induced expression of ORAIP in many neurons in a rat tandem occlusion model in vivo. In addition, we analyzed the effects of intracerebroventricular administration of neutralizing anti-ORAIP mAb on the development of cerebral infarction. Cerebral I/R significantly increased ORAIP levels in cerebrospinal fluid. Treatment with intracerebroventricular administration of neutralizing anti-ORAIP mAb reduced infarct volume by 72%, and by 55% even when started after reperfusion. These data strongly suggest that ORAIP plays a pivotal role and will offer a critical therapeutic target for cerebral I/R injury induced by thrombolysis and thrombectomy for acute ischemic stroke.