The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages
The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages
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DOI：
10.1007/s00540-009-0829-1
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发表时间：
2010-02-01
影响因子：
2.8
通讯作者：
Hirota, Kiichi
中科院分区：
文献类型：
--
作者：
Tanaka, Tomoharu;Takabuchi, Satoshi;Hirota, Kiichi
低氧诱导因子1(HIF-1)是低氧诱导基因表达的主要转录因子。据报道，麻醉药和围手术期药物会影响HIF-1的活性。然而，异丙酚对HIF-1活性的影响还没有很好的文献报道。在本研究中，我们研究了异丙酚对巨噬细胞分化的THP-1细胞HIF-1活化的影响。细胞暴露于20%或1%O-2条件下，加或不加异丙酚。用抗HIF-1α和HIF-1β抗体对细胞裂解产物进行Western印迹分析。用实时定量逆转录聚合酶链式反应和荧光素酶分析检测HIF-1依赖基因的表达。丙泊酚通过抑制HIF-1α蛋白的新合成，抑制脂多糖诱导的THP-1细胞中HIF-1α蛋白的积累，但对缺氧诱导的THP-1细胞中HIF-1α蛋白的合成无明显影响，且呈剂量依赖关系。丙泊酚可抑制HIF-1下游基因葡萄糖转运蛋白1、烯醇酶1、乳酸脱氢酶A、丙酮酸脱氢酶1和血管内皮生长因子的表达。异丙酚抑制脂多糖诱导的THP-1细胞乳酸蓄积和ATP含量。我们的实验结果表明，异丙酚可抑制脂多糖诱导的HIF-1激活和下游基因表达，并抑制HIF-1依赖的糖代谢重编程。异丙酚对巨噬细胞HIF-1的抑制可能解释了异丙酚抑制细胞炎症反应的分子机制。
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.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-1 alpha and HIF-1 beta 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.Propofol suppressed HIF-1 alpha 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-1 alpha 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.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.