Journal
JOURNAL OF NEUROCHEMISTRY
Volume 105, Issue 5, Pages 1849-1860Publisher
WILEY
DOI: 10.1111/j.1471-4159.2008.05287.x
Keywords
cerebral ischemia; glucose; hypoxia-inducible; factor 1; primary neuron; reactive oxygen species; redox status
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Funding
- NCRR NIH HHS [P20 RR15636] Funding Source: Medline
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It has been suggested that hypoxia-inducible factor 1 (HIF-1), a key regulator in cell's adaptation to hypoxia, plays an important role in the fate of neurons during ischemia. However, the mechanism of HIF-1 regulation is still not fully understood in neurons subjected to ischemia. In this study, we demonstrated that glucose up-regulated the expression of HIF-1 alpha, the oxygen-dependent subunit of HIF-1, in rat primary cortical neurons exposed to hypoxia. To understand the mechanism of glucose-regulated HIF-1 alpha expression, we investigated the relationships between HIF-1 alpha expression, reactive oxygen species (ROS), and redox status. Low levels of HIF-1 alpha protein expression were observed in the neurons exposed to in vitro ischemic conditions that had high levels of ROS (oxidizing environments), and vice versa. The glutathione (GSH) precursor, N-acetyl cysteine, induced HIF-1 alpha protein expression in hypoxic neurons while the GSH synthesis inhibitor, L-buthionine sulfoximine, inhibited the expression. Moreover, (-)-epicatechin gallate, a ROS scavenger, elevated HIF-1 alpha expression in the neurons subjected to in vitro ischemia. Furthermore, results from a systemic hypoxia model showed that a reducing environment increased HIF-1 alpha expression in rat brains. Taken together, these data presented the first evidence that glucose promoted HIF-lot stabilization through regulating redox status in primary neurons exposed to hypoxia. The results imply that hypoxia only may not be sufficient to stabilize HIF-lot and that a reducing environment is required to stabilize HIF-lot in neurons exposed to hypoxia.
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