Miralles C, Busquets X, Santos C, Togores B, Hussain S, Rahman I, MacNee W, Agustí A G
Unidad de Investigacion and the Servei de Pneumologia, Hospital Universitari Son Dureta, Palma de Mallorca, Spain.
FEBS Lett. 2000 Jul 7;476(3):253-7. doi: 10.1016/s0014-5793(00)01748-8.
Molecular oxygen (O(2)) regulates the expression of a variety of genes. We hypothesized that O(2) tension may regulate iNOS expression in rat liver through the production of reactive oxygen species (ROS) and the reduction of intracellular glutathione (GSH) levels. To investigate this hypothesis, we determined the effects of hyperoxia upon iNOS induction (both at the protein and mRNA level) and the intracellular concentration of GSH in an isolated in vitro perfused rat liver preparation. To study the potential involvement of ROS in the intracellular signaling pathway linking changes in oxygen tension to gene expression, we repeated these determinations in the presence of the thiol antioxidant N-acetyl-L-cysteine (NAC). We found that 95% O(2) tension caused a significant induction of the iNOS protein and mRNA levels paralleled by a significant fall in intracellular GSH concentration. The addition of NAC (1 mM) to the perfusate during hyperoxia blocked the induction of iNOS and restored GSH levels. These results indicate that molecular O(2) regulates the expression of iNOS in rat liver at the transcriptional level, most likely through the production of ROS and the reduction of intracellular GSH levels.
分子氧（O₂）可调节多种基因的表达。我们推测氧张力可能通过活性氧（ROS）的产生以及细胞内谷胱甘肽（GSH）水平的降低来调节大鼠肝脏中诱导型一氧化氮合酶（iNOS）的表达。为了验证这一推测，我们在离体灌注大鼠肝脏标本中，测定了高氧对iNOS诱导（蛋白质和mRNA水平）以及细胞内GSH浓度的影响。为了研究ROS在将氧张力变化与基因表达联系起来的细胞内信号通路中的潜在作用，我们在硫醇抗氧化剂N - 乙酰 - L - 半胱氨酸（NAC）存在的情况下重复了这些测定。我们发现，95%的氧张力可显著诱导iNOS蛋白质和mRNA水平，同时细胞内GSH浓度显著下降。在高氧期间向灌注液中添加NAC（1 mM）可阻断iNOS的诱导并恢复GSH水平。这些结果表明，分子氧在转录水平调节大鼠肝脏中iNOS的表达，很可能是通过ROS的产生以及细胞内GSH水平的降低来实现的。
