Department of Anesthesia, Kyoto University Hospital, Japan.
Antioxid Redox Signal. 2012 Feb 1;16(3):203-16. doi: 10.1089/ars.2011.3882. Epub 2011 Oct 17.
In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H(2)S) is an endogenously synthesized gaseous molecule that acts as an important signaling molecule in the living body. Transcription factor hypoxia-inducible factor 1 (HIF-1) is known to respond to intracellular reduced oxygen (O(2)) availability, which is regulated by an elaborate balance between O(2) supply and demand. However, the effect of H(2)S on HIF-1 activity under hypoxic conditions is largely unknown in mammalian cells. In this study, we tried to elucidate the effect of H(2)S on hypoxia-induced HIF-1 activation adopting cultured cells and mice.
The H(2)S donors sodium hydrosulfide and sodium sulfide in pharmacological concentrations reversibly reduced cellular O(2) consumption and inhibited hypoxia- but not anoxia-induced HIF-1α protein accumulation and expression of genes downstream of HIF-1 in established cell lines. H(2)S did not affect HIF-1 activation induced by the HIF-α hydroxylases inhibitors desferrioxamine or CoCl(2). Experimental evidence adopting von Hippel-Lindau (VHL)- or mitochondria-deficient cells indicated that H(2)S did not affect neosynthesis of HIF-1α protein but destabilized HIF-1α in a VHL- and mitochondria-dependent manner. We also demonstrate that exogenously administered H(2)S inhibited HIF-1-dependent gene expression in mice.
For the first time, we show that H(2)S modulates intracellular O(2) homeostasis and regulates activation of HIF-1 and the subsequent gene expression induced by hypoxia by using an in vitro system with established cell lines and an in vivo system in mice.
We demonstrate that H(2)S inhibits hypoxia-induced HIF-1 activation in a VHL- and mitochondria-dependent manner.
除一氧化氮和一氧化碳外，硫化氢（H₂S）也是一种内源性合成的气体分子，作为体内重要的信号分子发挥作用。转录因子缺氧诱导因子 1（HIF-1）已知对细胞内氧（O₂）的减少做出反应，这由 O₂供应和需求之间的精细平衡来调节。然而，在哺乳动物细胞中，H₂S 对低氧条件下 HIF-1 活性的影响在很大程度上是未知的。在这项研究中，我们试图通过培养细胞和小鼠来阐明 H₂S 对缺氧诱导的 HIF-1 激活的影响。
在药理浓度下，H₂S 供体硫氢化钠和硫化钠可逆地降低细胞的 O₂消耗，并抑制缺氧但不抑制缺氧诱导的 HIF-1α蛋白积累和 HIF-1 下游基因的表达在已建立的细胞系中。H₂S 不影响 HIF-1 激活诱导的 HIF-α羟化酶抑制剂去铁胺或 CoCl₂。采用 von Hippel-Lindau（VHL）或线粒体缺陷细胞的实验证据表明，H₂S 不影响 HIF-1α蛋白的新合成，但以 VHL 和线粒体依赖的方式使 HIF-1α不稳定。我们还证明，外源性给予的 H₂S 抑制了小鼠中 HIF-1 依赖性基因表达。
我们首次表明，H₂S 通过使用已建立的细胞系的体外系统和小鼠的体内系统，调节细胞内 O₂ 动态平衡，并调节 HIF-1 的激活以及随后由缺氧诱导的基因表达。
我们证明 H₂S 以 VHL 和线粒体依赖的方式抑制缺氧诱导的 HIF-1 激活。
