Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity
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- Sumi, Chisato
- Department of Anesthesiology, Kansai Medical University･Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Okamoto, Akihisa
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Tanaka, Hiromasa
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Kusunoki, Munenori
- Department of Anesthesiology, Kansai Medical University･Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Shoji, Tomohiro
- Department of Anesthesiology, Kansai Medical University･Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Uba, Takeo
- Department of Anesthesiology, Kansai Medical University･Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Adachi, Takehiko
- Department of Anesthesiology, Tazuke Kofukai Medical Research Institute
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- Iwai, Teppei
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Nishi, Kenichiro
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Harada, Hiroshi
- Laboratory of Cancer Cell Biology, Radiation Biology Center, Kyoto University･Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST)
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- Bono, Hidemasa
- Database Center for Life Science (DBCLS), Research Organization of Information and Systems (ROIS), Mishima
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- Matsuo, Yoshiyuki
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
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- Hirota, Kiichi
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University
Abstract
A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors.
Journal
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- Scientific Reports
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Scientific Reports 8 8987-, 2018-06-12
Springer Nature
