Treatment with hypoxia-mimetics protects cultured rat Schwann cells against oxidative stress-induced cell death
| Autor: | Nathan C. Boles, Brian T. David, David J C Coutts, Jessica J. Curtin, Caitlin E. Hill, Jennifer L Brown |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Programmed cell death Schwann cell Context (language use) Biology medicine.disease_cause 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine Animals Axon Cell Death Regeneration (biology) Peripheral Nervous System Diseases Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Axons Cell Hypoxia Cell biology Nerve Regeneration Rats Gene expression profiling Oxidative Stress 030104 developmental biology medicine.anatomical_structure Neurology Schwann Cells medicine.symptom 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | GliaREFERENCES. 69(9) |
| ISSN: | 1098-1136 |
| Popis: | Schwann cell (SC) grafts promote axon regeneration in the injured spinal cord, but transplant efficacy is diminished by a high death rate in the first 2-3 days postimplantation. Both hypoxic preconditioning and pharmacological induction of the cellular hypoxic response can drive cellular adaptations and improve transplant survival in a number of disease/injury models. Hypoxia-inducible factor 1 alpha (HIF-1α), a regulator of the cellular response to hypoxia, is implicated in preconditioning-associated protection. HIF-1α cellular levels are regulated by the HIF-prolyl hydroxylases (HIF-PHDs). Pharmacological inhibition of the HIF-PHDs mimics hypoxic preconditioning and provides a method to induce adaptive hypoxic responses without direct exposure to hypoxia. In this study, we show that hypoxia-mimetics, deferoxamine (DFO) and adaptaquin (AQ), enhance HIF-1α stability and HIF-1α target gene expression. Expression profiling of hypoxia-related genes demonstrates that HIF-dependent and HIF-independent expression changes occur. Analyses of transcription factor binding sites identify several candidate transcriptional co-regulators that vary in SCs along with HIF-1α. Using an in vitro model system, we show that hypoxia-mimetics are potent blockers of oxidative stress-induced death in SCs. In contrast, traditional hypoxic preconditioning was not protective. The robust protection induced by pharmacological preconditioning, particularly with DFO, indicates that pharmacological induction of hypoxic adaptations could be useful for promoting transplanted SC survival. These agents may also be more broadly useful for protecting SCs, as oxidative stress is a major pathway that drives cellular damage in the context of neurological injury and disease, including demyelinating diseases and peripheral neuropathies. |
| Databáze: | OpenAIRE |
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