The redox state of glutathione regulates the hypoxic induction of HIF-1.
The redox state of glutathione regulates the hypoxic induction of HIF-1.
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DOI：
10.1016/j.ejphar.2009.01.026
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发表时间：
2009-03
影响因子：
5
通讯作者：
M. Tajima;Y. Kurashima;K. Sugiyama;T. Ogura;H. Sakagami
中科院分区：
文献类型：
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作者：
M. Tajima;Y. Kurashima;K. Sugiyama;T. Ogura;H. Sakagami
缺氧诱导因子1（Hypoxia inducible factor 1，HIF-1）调节血管内皮生长因子（vascular endothelial growth factor，VEGF）的转录，在血管生成中起重要作用。我们研究了谷胱甘肽（GSH）对缺氧诱导人口腔鳞状细胞癌（HSC-2）细胞系中HIF-1的氧化还原作用。缺氧30 h后，HSC-2细胞中HIF-1的表达达到最高，36 h后，VEGFmRNA开始表达。GSH乙酯（GSHee，GSH的膜渗透性类似物）和N-乙酰基-L-半胱氨酸（NAC，GSH的膜渗透性前体）以剂量依赖性方式降低HIF-1结合活性。此外，GSHee和NAC类似地降低了HIF-1依赖性启动子活性。然而，依布硒啉，增加谷胱甘肽过氧化物酶的活性和氧化GSH，否定了GSHee对HIF-1依赖性启动子活性的影响。GSHee和NAC对HIF-1结合活性的抑制作用可被双（2-乙基）-亚硝基脲逆转，双（2-乙基）-亚硝基脲是一种氧化型谷胱甘肽（GSSG）还原酶抑制剂，可增加GSSG的浓度。GSSG甲酯（GSSGme），GSSG的膜渗透性类似物，增强HIF-1依赖的启动子活性，并表现出钟形的浓度依赖性活性曲线。在使用氯化钴获得的化学诱导的缺氧下也观察到GSSGme对HIF-1诱导的增加作用。这些结果表明，细胞内GSSG/GSH比例的变化可能调节缺氧诱导HIF-1。
Hypoxia inducible factor 1 (HIF-1) regulates the transcription of vascular endothelial growth factor (VEGF), which plays important roles in angiogenesis. We investigated the redox effect of glutathione (GSH) on the hypoxic induction of HIF-1 in a human oral squamous cell carcinoma (HSC-2) cell line. The maximal induction of HIF-1 in HSC-2 cells was observed 30 h after hypoxia, and VEGF mRNA was expressed after 36 h under hypoxia. GSH ethyl ester (GSHee, a membrane permeable analog of GSH) and N-acetyl-L-cysteine (NAC, a membrane permeable precursor of GSH) reduced HIF-1 binding activity in a dose-dependent manner. Further, HIF-1 dependent promoter activity was similarly reduced by GSHee and NAC. However, ebselen, which increases glutathione peroxidase activity and oxidizes GSH, negated the effect of GSHee on HIF-1 dependent promoter activity. The inhibitory effect of GSHee and NAC on HIF-1 binding activity was reversed by bis (2-chlorethyl)-nitrosourea, an oxidized glutathione (GSSG) reductase inhibitor which increases the concentration of GSSG. GSSG methyl ester (GSSGme), a membrane permeable analog of GSSG, enhanced HIF-1 dependent promoter activity and exhibited a bell-shaped concentration-dependant activity curve. The increasing effect of GSSGme on HIF-1 induction was also observed under chemically-induced hypoxia obtained using cobalt chloride. These results suggest that changes in the intracellular GSSG/GSH ratio may regulate HIF-1 induction during hypoxia.