The intravenous anesthetics barbiturates inhibit hypoxia-inducible factor 1 activation.

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor of hypoxia-induced gene expression. Anesthetics and perioperative drugs have been reported to affect HIF-1 activity. However, the effect of barbiturates on HIF-1 activity has not been reported. In this study, we investigated the effect of thiopental and thiamylal on HIF-1 activity using the neuronal SH-SY5Y cells, the non-neuronal HEK293 cells, and the macrophage-differentiated THP-1 cells. Cells were exposed to 20% or 1% O(2) conditions with or without thiopental or thiamylal treatment. The cell lysate were subjected to Western blot analysis using anti-HIF-1alpha and -HIF-1beta antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time RT-PCR and luciferase assay. Hydroxylation of HIF-1alpha protein was evaluated by in vitro pulldown assay using recombinant protein. Both thiopental and thiamylal reversibly suppressed hypoxia-induced HIF-1 activation in the neuronal and the non-neuronal cells in a dose-dependent manner. Moreover, the barbiturates inhibited lipopolysaccharide-induced HIF-1alpha expression in THP-1 cells. The HIF-1-downstream gene expression was also inhibited by the barbiturates. HIFalpha-hydroxylases activity and HIF-1alpha stability were not affected but the HIF-1alpha protein neosynthesis was inhibited by the barbiturates. Our experimental results indicate that barbiturates inhibit induced HIF-1 activation and downstream genes expression.

• Authors: Takuhiko Wakamatsu, Tomoharu Tanaka, Seiko Oda, Kenichiro Nishi, Hiroshi Harada, Hiroki Daijo, Satoshi Takabuchi, Shinichi Kai, Kazuhiko Fukuda, Kiichi Hirota
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 617 Issue 1-3 Pg. 17-22 (Sep 01 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19595685 (Publication Type: Journal Article)

Chemical References

• ARNT protein, human
• Anesthetics
• Barbiturates
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Oxygen
• barbituric acid

Topics

• Anesthesia, Intravenous
• Anesthetics (administration & dosage, pharmacology)
• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (biosynthesis, chemistry, genetics)
• Barbiturates (administration & dosage, pharmacology)
• Cell Line
• Dose-Response Relationship, Drug
• Humans
• Hypoxia-Inducible Factor 1 (biosynthesis, chemistry, genetics)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, chemistry, genetics)
• Neurons (drug effects, metabolism)
• Oxygen (metabolism)
• Protein Stability (drug effects)
• Transcriptional Activation (drug effects)