Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1α and erythropoietin in rats
Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1α and erythropoietin in rats
复制标题
高压氧预处理诱导大鼠缺血耐受的机制涉及上调缺氧诱导因子-1α和促红细胞生成素。
DOI：
10.1152/japplphysiol.00323.2007
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Sun, Xue-Jun
中科院分区：
文献类型：
--
作者：
Gu, Guo-Jun;Li, Yun-Ping;Sun, Xue-Jun
本研究采用大鼠局灶性脑缺血模型，探讨高压氧（HBO）预处理对脑保护作用的分子机制。72只雄性Sprague-Dawley大鼠用HBO（100%O（2），2个大气压绝对压力，每隔一天1小时，共5次）或室内空气预处理。在实验1中，HBO预处理的大鼠和匹配的室内空气对照进行局灶性脑缺血或假手术。损伤后的运动参数和梗死体积HBO预处理大鼠与对照组进行了比较。在实验2中，HBO预处理的大鼠和匹配的室内空气对照在不同的时间点被杀死。通过Western blotting和RT-PCR分析缺氧诱导因子-1 α（HIF-1 α）及其下游靶基因促红细胞生成素（EPO）的脑水平，以及HIF-1 α DNA结合和转录活性在同侧半球进行测定。HBO可诱导HIF-1 α、EPO蛋白表达及HIF-1 α活性明显升高，EPO mRNA表达也明显增加。高压氧预处理显著改善了各时间点的神经行为学结果（4 h时3.0 +/- 2.1 vs. 5.6 +/- 1.5，8 h时5.0 +/- 1.8 vs. 8.8 +/- 1.4，24 h时6.4 +/- 1.8 vs. 9.7 +/- 1.3; P < 0.01）和减少脑缺血后的梗死体积（20.7 +/- 4.5 vs. 12.5 +/-3.6%，2，3，5-氯化三苯基四氮唑染色）。提示HBO预处理诱导的神经保护作用可能是通过上调HIF-1 α及其靶基因EPO的表达而实现的。
We studied the effect of hyperbaric oxygen (HBO) preconditioning on the molecular mechanisms of neuroprotection in a rat focal cerebral ischemic model. Seventy-two male Sprague-Dawley rats were pretreated with HBO (100% O(2), 2 atmospheres absolute, 1 h once every other day for 5 sessions) or with room air. In experiment 1, HBO-preconditioned rats and matched room air controls were subjected to focal cerebral ischemia or sham surgery. Postinjury motor parameters and infarction volumes of HBO-preconditioned rats were compared with those of controls. In experiment 2, HBO-preconditioned rats and matched room air controls were killed at different time points. Brain levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream target gene erythropoietin (EPO) analyzed by Western blotting and RT-PCR as well as HIF-1alpha DNA-binding and transcriptional activities were determined in the ipsilateral hemisphere. HBO induced a marked increase in the protein expressions of HIF-1alpha and EPO and the activity of HIF-1alpha, as well as the expression of EPO mRNA. HBO preconditioning dramatically improved the neurobehavioral outcome at all time points (3.0 +/- 2.1 vs. 5.6 +/- 1.5 at 4 h, 5.0 +/- 1.8 vs. 8.8 +/- 1.4 at 8 h, 6.4 +/- 1.8 vs. 9.7 +/- 1.3 at 24 h; P < 0.01, respectively) and reduced infarction volumes (20.7 +/- 4.5 vs. 12.5 +/- 3.6%, 2,3,5-Triphenyltetrazolium chloride staining) after cerebral ischemia. This observation indicates that the neuroprotection induced by HBO preconditioning may be mediated by an upregulation of HIF-1alpha and its target gene EPO.