| Specific inhibition of hypoxia inducible factor 1 exaggerates cell injury induced by in vitro ischemia through deteriorating cellular redox environment. | |
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MedLine Citation:
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PMID: 19183269 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia inducible factor 1 (HIF-1) has been suggested to play a critical role in the fate of cells exposed to hypoxic stress. However, the mechanism of HIF-1-regulated cell survival is still not fully understood in ischemic conditions. Redox status is critical for decisions of cell survival, death and differentiation. We investigated the effects of inhibiting HIF-1 on cellular redox status in SH-SY5Y cells exposed to hypoxia or oxygen and glucose deprivation (OGD), coupled with cell death analyses. Our results demonstrated that inhibiting HIF-1alpha expression by HIF-1alpha specific small interfering RNA (siRNA) transfection increased reactive oxygen species generation, and transformed the cells to more oxidizing environments (low GSH/GSSG ratio, low NADPH level) under either hypoxic or OGD exposure. Cell death increased dramatically in the siRNA transfected cells, compared to non-transfected cells after hypoxic/OGD exposures. In contrast, increasing HIF-1alpha expression by desferrioxamine, a metal chelator and hydroxylase inhibitor, induced a more reducing environment (high GSH/GSSG ratio, high NADPH level) and reduced cell death. Further studies showed that HIF-1 regulated not only glucose transporter-1 expression, but also the key enzymes of the pentose phosphate pathway such as glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. These enzymes are important in maintaining cellular redox homeostasis by generating NADPH, the primary reducing agent in cells. Moreover, catalase significantly decreased cell death in the siRNA-transfected cells induced by hypoxia and OGD. These results suggest that maintenance of cellular redox status by HIF-1 protects cells from hypoxia and ischemia mediated injuries. |
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Authors:
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Shuhong Guo; Minoru Miyake; Ke Jian Liu; Honglian Shi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-01-29 |
Journal Detail:
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Title: Journal of neurochemistry Volume: 108 ISSN: 1471-4159 ISO Abbreviation: J. Neurochem. Publication Date: 2009 Mar |
Date Detail:
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Created Date: 2009-03-23 Completed Date: 2009-04-22 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: England |
Other Details:
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Languages: eng Pagination: 1309-21 Citation Subset: IM |
Affiliation:
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University of New Mexico Health Sciences Center, Albuquerque, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Cell Death / drug effects Cell Hypoxia / drug effects, physiology* Cell Line, Tumor Deferoxamine / pharmacology Enzyme-Linked Immunosorbent Assay Gene Expression Regulation, Neoplastic / drug effects Glucose / deficiency Glucose Transporter Type 1 / metabolism Glutathione / metabolism Glutathione Disulfide / metabolism Humans Hypoxia-Inducible Factor 1 / antagonists & inhibitors, genetics, metabolism* L-Lactate Dehydrogenase / metabolism NADP / metabolism Neuroblastoma Oxidation-Reduction / drug effects RNA, Small Interfering / genetics, metabolism Reactive Oxygen Species / metabolism Siderophores / pharmacology Transcriptional Activation Transfection / methods |
| Grant Support | |
ID/Acronym/Agency:
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P20 RR15636/RR/NCRR NIH HHS; R01 NS058807-01A1/NS/NINDS NIH HHS; R01NS058807/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glucose Transporter Type 1; 0/Hypoxia-Inducible Factor 1; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Siderophores; 27025-41-8/Glutathione Disulfide; 50-99-7/Glucose; 53-59-8/NADP; 70-18-8/Glutathione; 70-51-9/Deferoxamine; EC 1.1.1.27/L-Lactate Dehydrogenase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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