Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin
Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin
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DOI：
10.1161/01.str.0000080381.76409.b2
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发表时间：
2003-08-01
期刊：
影响因子：
8.3
通讯作者：
Meisel, A
中科院分区：
文献类型：
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作者：
Prass, K;Scharff, A;Meisel, A
背景和目的细胞对缺氧的反应主要由缺氧诱导因子1（HIF-1）控制。HIF-1靶基因促红细胞生成素（EPO）已被描述为具有神经保护作用。因此，我们假设EPO是一个必不可少的调解人的保护，在低氧precondition. Methods，我们将Sv 129小鼠随机分组为不同的预处理，不同的缺氧缺血时间间隔，或不同的缺血时间。对于低氧预适应，动物暴露于低氧气体混合物（8%O-2和92%N-2）30，60，180，300或360分钟。在0、24、48、72或144小时后，我们进行大脑中动脉闭塞，并在30、45、60或120分钟后允许再灌注，或者永久性闭塞。我们研究了EPO基因在脑组织中的表达与实时逆转录聚合酶链反应和测量HIF-1 DNA结合活性与电泳迁移率变动分析。为了阻止内源性产生的EPO，我们滴入可溶性EPO受体到cerebral ventriculum. Results-Hypoprotein预处理180或300分钟诱导相对耐受短暂的局灶性脑缺血，证明了梗死体积减少到75%或54%的控制，分别。低渗预处理仅在大脑中动脉闭塞前48或72小时有效。缺氧60分钟后，我们发现HIF-1 DNA结合活性显著激活，EPO转录诱导7倍。输注可溶性EPO受体显着降低了40%.Conclusions缺氧预处理的保护作用，内源性产生的EPO是缺血预处理的重要介质。
Background and Purpose-Cellular response to hypoxia is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The HIF-1 target gene erythropoietin (EPO) has been described as neuroprotective. Thus, we hypothesize EPO to be an essential mediator of protection in hypoxic preconditioning.Methods-We randomized Sv129 mice into groups for different pretreatments, different hypoxia-ischemia intervals, or different durations of ischemia. For hypoxic preconditioning, the animals were exposed to a hypoxic gas mixture (8% O-2 and 92% N-2) for 30, 60, 180, 300, or 360 minutes. At 0, 24, 48, 72, or 144 hours later, we performed middle cerebral artery occlusion and allowed reperfusion after 30, 45, 60, or 120 minutes, or occlusion was left to be permanent. We studied EPO gene expression in brain tissue with a real-time reverse transcriptase-polymerase chain reaction and measured HIF-1 DNA-binding activity with an electrophoretic mobility shift assay. To block endogenously produced EPO, we instilled soluble EPO receptor into the cerebral ventricle.Results-Hypoxic preconditioning for 180 or 300 minutes induced relative tolerance to transient focal cerebral ischemia, as evidenced by a reduction of infarct volumes to 75% or 54% of the control, respectively. Hypoxic pretreatment was effective only when applied 48 or 72 hours before middle cerebral artery occlusion. Sixty minutes after hypoxia, we found a marked activation of HIF-1 DNA-binding activity and a 7-fold induction of EPO transcription. Infusion of soluble EPO receptor significantly reduced the protective effect of hypoxic pretreatment by 40%.Conclusions-Endogenously produced EPO is an essential mediator of ischemic preconditioning.