Abstract
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.
Highlights
Stroke is the worldwide leading cause of severe morbidity and mortality in the elderly and causes 9% of all deaths around the world, representing the second most common cause of death after ischemic heart disease
We reported that plasma oxidative stress-responsive apoptosis inducing protein” (ORAIP) levels were significantly elevated in chronic diseases such as chronic kidney disease, diabetes mellitus, and atrial fibrillation, in which oxidative stress is critically involved in the pathogenesis[30,31,32]
We examined the induction of ORAIP in cerebral neurons subjected to hypoxia/reoxygenation by double-immunostaining for ORAIP and the neuron-specific neuronal nuclei (NeuN) antigen, showing that most cells were neurons (Fig. 1A)
Summary
Stroke is the worldwide leading cause of severe morbidity and mortality in the elderly and causes 9% of all deaths around the world, representing the second most common cause of death after ischemic heart disease. There are many reasons why antioxidants have failed in clinical trials, such unexpected findings have raised the possibility that unknown mechanisms other than ROS may be mediating oxidative stress-induced cell injury. We previously reported that a novel post-translationally modified eukaryotic translation initiation factor 5 A (eIF5A) is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation and acts as the apoptosis-inducing factor in an autocrine fashion[28]. We refer to this novel tyrosine-sulfated secreted form of eIF5A as “oxidative stress-responsive apoptosis inducing protein” (ORAIP)[28]. We show that ORAIP plays a pivotal role in a rat model of cerebral I/R injury, offering a novel efficacious prevention therapy against cerebral I/R injury
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