Effect of nuclear glutathione on DNA damage by irradiation

氧化低密度脂蛋白（oxLDL）在动脉粥样硬化发病机制中改变巨噬细胞炎症反应。在本研究中，我们专注于γ-谷氨酰半胱氨酸合成酶（γ-GCS），谷胱甘肽合成的限速酶，并检查是否修饰的γ-GCS基因的炎症刺激巨噬细胞的脂多糖（LPS）时，细胞暴露于oxLDL。我们发现，核因子-κ B（NF-κ B）介导的γ-GCS诱导LPS（100 ng/ml）抑制48小时的预处理与oxLDL（50 μ g/ml），这是由于NF-κ B的DNA结合活性的降低。此外，用oxLDL预处理引起NF-κ B亚基p65的羰基化。使用α-生育酚时，oxLDL诱导的蛋白质羰基化降低，NF-κ B的DNA结合活性恢复。总之，这些表明NF-κ B的氧化修饰抑制了ox-LDL处理的细胞中LPS诱导的γ-GCS基因的表达，提示了oxLDL诱导的NF-κ B信号转导的调节与动脉粥样硬化的关系。

Oxidized low-density lipoprotein (oxLDL) modifies macrophage inflammatory responses in the pathogenesis of atherosclerosis. In the present study, we focused on gamma-glutamylcysteine synthetase (gamma-GCS), a rate limiting enzyme of glutathione synthesis, and examined whether inflammatory stimulation of gamma-GCS gene in macrophages by lipopolysaccharide(LPS) is modified when the cells were exposed to oxLDL. We found that the nuclear factor-kappa B(NF-kappa B)-mediated induction of gamma-GCS by LPS (100 ng/ml) was suppressed by a 48-h pre-treatment with oxLDL (50 micro/ml), and this was due to a decrease in the DNA-binding activity of NF-kappa B. Furthermore, pre-treatment with oxLDL caused a carbonylation of NF-kappa B subunit p65. With alpha-tocopherol, the oxLDL-induced carbonylation of proteins decreased with a restoration of DNA-binding activity of NF-kappa B. Together, these indicate that oxidative modification of NF-kappa B suppresses LPS-induced expression of gamma-GCS gene in ox-LDL-treated cells, suggesting an implication of oxLDL-induced modulation of NF-kappa B signaling with atherosclerosis.