Calvert John W, Cahill Julian, Yamaguchi-Okada Mitsuo, Zhang John H
Division of Neurosurgery, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
J Appl Physiol (1985). 2006 Sep;101(3):853-65. doi: 10.1152/japplphysiol.00268.2006. Epub 2006 May 25.
Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.
最近，越来越多的证据表明，在实验性全脑缺血和蛛网膜下腔出血后，高压氧疗（HBOT）诱导的神经保护作用会导致缺氧诱导因子-1α（HIF-1α）表达降低。因此，本研究的目的是验证以下假设：新生儿缺氧缺血后氧诱导的神经保护作用涉及HIF-1α表达的改变。对7日龄大鼠幼崽进行单侧颈动脉结扎，随后在37℃下缺氧2小时（8%氧气）。然后对幼崽进行2小时的HBOT（2.5ATA）或常压氧疗（NBOT）。在损伤后长达24小时的时间间隔内评估HIF-1α的表达和磷酸化状态，以及葡萄糖转运蛋白（GLUT）-1、GLUT-3、乳酸脱氢酶（LDH）、醛缩酶（Ald）和p53的表达。还检测了HIF-1α与p53的蛋白质-蛋白质相互作用。损伤后观察到HIF-1α、GLUT-1、GLUT-3、Ald和LDH的表达升高。HIF-1α去磷酸化形式增加后，HIF-1α与p53的结合增加，p53水平升高。HBOT和NBOT均降低了HIF-1α的升高表达并降低了其去磷酸化形式。此外，两种治疗均促进了GLUT-1、GLUT-3、LDH和Ald表达的短暂增加，同时减少了HIF-1α-p53相互作用并降低了p53的表达。因此，单次氧疗改变HIF-1α表型可能是新生儿缺氧缺血损伤后给予氧气时观察到的氧诱导神经保护作用的潜在机制之一。
