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Monitoring Astrocyte Reactivity and Proliferation in Vitro Under Ischemic-Like Conditions
Published on: October 21, 2017
Hypoxia stabilizes type 2 deiodinase activity in rat astrocytes
Audrey Lamirand1, Gilles Mercier, Martine Ramaugé
1Institut National de la Santé et de la Recherche Médicale, UMR 854, and Université Paris-Sud 11, 80 Rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France.
Endocrinology
|July 7, 2007
Summary
Hypoxia increases type 2 deiodinase (D2) activity in brain astrocytes by stabilizing the enzyme post-translationally, likely via proteasome pathway inhibition. This suggests a novel mechanism for regulating thyroid hormone levels during oxygen deprivation.
Area of Science:
- Neuroendocrinology
- Cellular Physiology
Background:
- Thyroid hormone activation is crucial for brain function.
- Type 2 deiodinase (D2) catalyzes the conversion of thyroxine (T4) to triiodothyronine (T3) in the brain.
- D2 is rapidly induced in astrocytes following ischemic events.
Purpose of the Study:
- To investigate the effects of hypoxia on D2 activity in cultured astrocytes.
- To elucidate the molecular mechanisms underlying hypoxia-induced D2 regulation.
Main Methods:
- Primary astrocyte cultures were exposed to hypoxia (2.5% O2).
- D2 activity, mRNA levels, and protein stability were assessed.
- Pharmacological inhibitors of proteasomes, prolyl hydroxylases, signaling pathways, and NADPH oxidase were utilized.
Main Results:
- Hypoxia significantly increased D2 activity without altering mRNA levels.
- Cycloheximide experiments indicated a post-translational mechanism.
- Hypoxia enhanced D2 half-life and its effect was not additive with proteasome inhibitors, suggesting reduced degradation.
- Hypoxia-induced D2 stabilization was partially mediated by prolyl hydroxylase inhibition and reactive oxygen species, involving NADPH oxidase.
Conclusions:
- Hypoxia stabilizes D2 protein in astrocytes, primarily by inhibiting proteasomal degradation.
- This post-translational regulation is independent of D2 gene expression.
- Reactive oxygen species and prolyl hydroxylase pathways are implicated in hypoxia-induced D2 stabilization.
