The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages.
OBJECTIVE
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 propofol on HIF-1 activity is not well documented. In this study, we investigated the effect of propofol on HIF-1 activation using macrophage-differentiated THP-1 cells.


METHODS
Cells were exposed to lipopolysaccharide (LPS) under 20 or 1% O(2) conditions with or without propofol treatment. The cell lysate was subjected to Western blot analysis using anti-HIF-1alpha and HIF-1beta antibodies. HIF-1-dependent gene expression was investigated by quantitative real-time reverse-transcriptase PCR analysis and luciferase assay. The amount of cellular lactate and ATP was assayed.


RESULTS
Propofol suppressed HIF-1alpha protein accumulation induced by LPS, but not by hypoxia in the THP-1 cells in a dose-dependent manner by inhibiting the neo-synthesis of HIF-1alpha protein. Induction of the HIF-1 downstream gene expression including glucose transporter 1, enolase 1, lactate dehydrogenase A, pyruvate dehydrogenase kinase-1 and vascular endothelial growth factor was inhibited by propofol. Propofol suppressed LPS-induced lactate accumulation and ATP content in THP-1 cells.


CONCLUSIONS
Our experimental results indicate that propofol inhibits HIF-1 activation and downstream gene expression induced by LPS and suppressed HIF-1-dependent glucose metabolic reprogramming. HIF-1 suppression by propofol in macrophages may explain molecular mechanisms behind the inhibitory effect of propofol on cellular inflammatory responses.
Tanaka
Tomoharu
T
Department of Anesthesia, Kyoto University Hospital, 54 Shogoin-Kawaracho, Sakyo-Ku, Kyoto, 6060-8507, Japan.
Takabuchi
Satoshi
S
Nishi
Kenichiro
K
Oda
Seiko
S
Wakamatsu
Takuhiko
T
Daijo
Hiroki
H
Fukuda
Kazuhiko
K
Hirota
Kiichi
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism
C497396:ARNT protein, human; D018686:Anesthetics, Intravenous; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015853:Cysteine Proteinase Inhibitors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D015742:Propofol