The effects of local anesthetics on cellular hypoxia-induced gene responses mediated by hypoxia-inducible factor 1.
OBJECTIVE
Hypoxia (reduced oxygen availability) induces a series of adaptive physiological responses. At the cellular level, the adaptation includes a switch of energy metabolism from oxidative phosphorylation to anaerobic glycolysis, increased glucose uptake, and the expression of stress proteins related to cell survival. One of the most important transcription factors that activate the expression of oxygen-regulated genes is hypoxia-inducible factor 1 (HIF-1). We previously reported that halothane inhibits the hypoxia-induced HIF-1 activation. In this study, we investigated the effect of local anesthetics on HIF-1 activation and its downstream gene expression.


METHODS
The established cell line Hep3B and SK-N-MC cells were exposed to 1% O2 with or without treatment by either lidocaine or bupivacaine. Expression of subunits of HIF-1, HIF-1alpha, and HIF-1beta was examined by Western blot using specific antibodies. Expression of mRNA of HIF-1 and the HIF-1-dependent genes was investigated by RT-PCR and reporter assay.


RESULTS
Neither of the local anesthetics tested affected the accumulation of HIF-1alpha induced by hypoxia, nor did they affect NOC18-induced HIF-1alpha accumulation. Moreover, they had no effects on HIF-1-mediated hypoxia-induced gene expression.


CONCLUSIONS
The local anesthetics lidocaine and bupivacaine did not affect the HIF-1-dependent cellular hypoxia-induced gene responses.
Nishi
Kenichiro
K
Department of Anesthesia, The Tazuke Kofukai Medical Research Institute Kitano Hospital, 2-4-20 Ohgi-machi, Kita-ku, Osaka, 530-8480, Japan.
Hirota
Kiichi
K
Takabuchi
Satoshi
S
Oda
Seiko
S
Fukuda
Kazuhiko
K
Adachi
Takehiko
T
Shingu
Koh
K
D000779:Anesthetics, Local / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D017930:Genes, Reporter; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D009569:Nitric Oxide / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000779:Anesthetics, Local; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; D006221:Halothane