Role of nitric oxide in the regulation of HIF-1α expression during hypoxia
Role of nitric oxide in the regulation of HIF-1α expression during hypoxia
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DOI：
10.1152/ajpcell.00381.2001
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发表时间：
2002-07-01
影响因子：
5.5
通讯作者：
LaManna, J
中科院分区：
文献类型：
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作者：
Agani, FH;Puchowicz, M;LaManna, J
缺氧诱导因子-1 （Hypoxia-inducible factor-1, HIF-1）是一种异二聚体转录因子，由HIF-1 α和HIF-1 β亚基组成，控制大量参与调节细胞对缺氧反应的基因的表达。氧调节亚基hif -1 α在暴露于缺氧的细胞中是稳定的。一氧化氮（NO）对缺氧反应的调节被认为具有广泛的病理生理相关性，因此我们研究了NO是否影响缺氧细胞中HIF-1的激活。本研究表明，一氧化氮供体产生的一氧化氮可阻止Hep 3B和PC-12细胞中hif -1 α缺氧积累。添加谷胱甘肽类似物或过氧亚硝酸盐清除剂可防止no诱导的hif -1 α积累的抑制。暴露于NO与线粒体电子传递和代偿性糖酵解的抑制有关，这维持了正常的细胞ATP含量。琥珀酸盐，一种克雷布斯循环中间体和呼吸链底物，在细胞中恢复了hif -1 α缺氧诱导，提示线粒体参与了缺氧时hif -1 α积累的调节。NO调节hif -1 α是NO调节哺乳动物细胞缺氧反应的另一个重要机制。
Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor consisting of HIF-1alpha and HIF-1beta subunits, controls the expression of a large number of genes involved in the regulation of cellular responses to reduced oxygen availability. The oxygen-regulated subunit, HIF-1alpha, is stabilized in cells exposed to hypoxia. The regulation of hypoxic responses by nitric oxide (NO) is believed to have wide pathophysiological relevance, thus we investigated whether NO affects HIF-1 activation in hypoxic cells. Here we show that NO generated from NO donors prevented HIF-1alpha hypoxic accumulation in Hep 3B and PC-12 cells. Addition of a glutathione analog or peroxynitrite scavengers prevented the NO-induced inhibition of HIF-1alpha accumulation in both cell lines. Exposure to NO was associated with inhibition of mitochondrial electron transport and compensatory glycolysis, which maintained normal cellular ATP content. Succinate, a Krebs cycle intermediate and respiratory chain substrate, restored HIF-1alpha hypoxic induction in the cells, suggesting involvement of mitochondria in regulation of HIF-1alpha accumulation during hypoxia. Regulation of HIF-1alpha by NO is an additional important mechanism by which NO might modulate cellular responses to hypoxia in mammalian cells.