Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity.
Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity.
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DOI：
10.1038/s41598-018-27220-8
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发表时间：
2018-06-12
影响因子：
4.6
通讯作者：
Hirota K
中科院分区：
文献类型：
--
作者：
Sumi C;Okamoto A;Tanaka H;Kusunoki M;Shoji T;Uba T;Adachi T;Iwai T;Nishi K;Harada H;Bono H;Matsuo Y;Hirota K
一系列研究强烈表明，静脉麻醉剂异丙酚抑制线粒体的氧代谢。研究还表明，异丙酚诱导细胞死亡的方式依赖于活性氧(ROS)。由于缺氧诱导因子1(HIF-1)是一种转录因子，通过调节糖酵解途径和线粒体氧利用等酶的基因表达而参与细胞代谢重编程，因此我们研究了HIF-1活性在异丙酚诱导的细胞死亡中的作用。在肾细胞来源的RCC4细胞、表达von Hippel-Lindau蛋白(VHL)的RCC4-EV细胞和表达外源性VHL的RCC4-VHL细胞以及神经细胞SH-SY5Y细胞中，研究了HIF-1活性在氧和能量代谢、异丙酚诱导的细胞死亡和caspase活性中的作用。研究表明，HIF-1参与抑制细胞的氧耗和促进糖酵解，并且对异丙酚诱导的细胞死亡的抵抗是以HIF-1激活依赖的方式建立的。用α羟化酶抑制剂如没食子酸丙酯和甘氨酸二甲氧甲酯处理缺氧诱导因子-1，可减轻异丙酚的毒性作用。因此，对异丙酚毒性的抵抗是由于HIF-1激活，不仅通过VHL的基因缺失，而且还通过暴露于HIFα羟基酶抑制剂来实现。
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.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
二甲双胍的线粒体靶向类似物在胰腺癌细胞中表现出增强的抗增殖和放射增敏作用。
影响因子：
11.2
作者：
Cheng G;Zielonka J;Ouari O;Lopez M;McAllister D;Boyle K;Barrios CS;Weber JJ;Johnson BD;Hardy M;Dwinell MB;Kalyanaraman B
通讯作者：
Kalyanaraman B
DOI：
10.1111/j.1432-1033.1974.tb03899.x
发表时间：
1974-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
NICHOLLS, DG
通讯作者：
NICHOLLS, DG