Antioxidants, HIF Prolyl Hydroxylase Inhibitors or Short Interfering RNAs to BNIP3 or PUMA, Can Prevent Prodeath Effects of the Transcriptional Activator, HIF-1α, in a Mouse Hippocampal Neuronal Line
- 1 December 2008
- journal article
- research article
- Published by Mary Ann Liebert Inc in Antioxidants and Redox Signaling
- Vol. 10 (12), 1989-1998
- https://doi.org/10.1089/ars.2008.2039
Abstract
Hypoxia-inducible factor (HIF) is a transcriptional activator that promotes death or survival in neurons. The regulators and targets of HIF-1α–mediated death remain unclear. We found that prodeath effects of HIF-1 are not attributable to an imbalance in HIF-1α and HIF-1β expression. Rather, the synergistic death caused by oxidative stress and by overexpression of an oxygen-resistant HIF-VP16 in neuroblasts was attributable to transcriptional upregulation of BH3-only prodeath proteins, PUMA or BNIP3. By contrast, overexpression of BNIP3 was not sufficient to potentiate oxidative death. As acidosis is known to activate BNIP3-mediated death, we examined other secondary stresses, such as oxidants or prolyl hydroxylase activity are necessary for exposing the prodeath functions of HIF in neurons. Antioxidants or prolyl hydroxylase inhibition prevented potentiation of death by HIF-1α. Together, these studies suggest that antioxidants and PHD inhibitors abrogate the ability of HIF-mediated transactivation of BH3-only proteins to potentiate oxidative death in normoxia. The findings offer strategies for minimizing the prodeath effects of HIF-1 in neurologic conditions associated with hypoxia and oxidative stress, such as stroke and spinal cord injury. Antioxid. Redox Signal. 11, 1989–1998.Keywords
This publication has 33 references indexed in Scilit:
- Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to HypoxiaJournal of Biological Chemistry, 2008
- Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal ApoptosisJournal of Neuroscience, 2007
- Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in miceJCI Insight, 2007
- BNIP3 Is an RB/E2F Target Gene Required for Hypoxia-Induced AutophagyMolecular and Cellular Biology, 2007
- BNIP3 Upregulation and EndoG Translocation in Delayed Neuronal Death in Stroke and in HypoxiaStroke, 2007
- Prosurvival and Prodeath Effects of Hypoxia-inducible Factor-1α Stabilization in a Murine Hippocampal Cell LinePublished by Elsevier BV ,2005
- p53 Activation Domain 1 Is Essential for PUMA Upregulation and p53-Mediated Neuronal Cell DeathJournal of Neuroscience, 2004
- Hypoxia-inducible Factor 1α (HIF-1α) Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic ConditionsPublished by Elsevier BV ,1997
- Activation of Hypoxia-inducible Transcription Factor Depends Primarily upon Redox-sensitive Stabilization of Its α SubunitPublished by Elsevier BV ,1996