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Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1 and its downstream target genes

¹Department of Physiology and Pharmacology, ²Division of Neurosurgery, and ³Department of Anesthesiology, Loma Linda University Medical Center, Loma Linda, California

Submitted 1 March 2006 ; accepted in final form 12 May 2006

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-1 (HIF-1). 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-1. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O₂ at 37°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-1 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-1 and p53 was also examined. An elevated expression of HIF-1, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1 was followed by an increase in the association of HIF-1 with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1 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-1-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1 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.

brain; hyperbaric oxygenation; hypoxia-inducible factor-1; normobaric oxygenation; neonatal hypoxia-ischemia

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