A role of amino acid metabolism in the oxidative stress response

我们发现了一个在Aldehydes升高水平的慢性暴露中对转基因老鼠暴露的增强性心脏造影术的交叉口。该机制被揭示为，因为它是一种选择性的向上调节，即eIF 2 α α-α-有机表达的一组基因，它包含在氨基酸生物合成和对氧化应激的抵抗力。However，一个基本的关键点仍然是未知的，即如何感知到aldehydes在一个定量标记中刺激磷酸化的eIF 2 α。在这项研究中，我们揭示了自由历史的内在水平被选择性地降低了50%，在心脏暴露到Aldehydes的升高水平。在特定情况下，氨基酸缺陷传感器，GCN 2（一般控制非持久-2），是eIF 2的一种，已激活。有趣的是，通过喂养高组织饮食减少GCN 2和eIF 2的磷酸化水平的正常化，结果在ATF 4介导的基因表达和心脏起搏器对抗化学反应的补充。4-羟基-2-非线性直接反应组蛋白到降解内游离组蛋白水平，在eIF 2·野生型细胞中进行磷酸化处理，但不在GCN 2 ^<-/->细胞中。Thus，GCN 2在定量标记中感觉到aldehyde压力，通过监测一个不含内部历史水平的decline。这一定是一个新颖而常见的计划，是氧化压力的重要传感器。

We by contraries found that chronic exposure of aldehydes enhanced cardioprotection against ischemia-reperfusion injury in the transgenic mice exposed to elevated levels of aldehydes. The mechanism was revealed as that selective up-regulation of Atf4 under phosphorylation of eIF2α coordinately expressed sets of genes that are involved in amino acid biosynthesis and resistance to oxidative stress. However, an essential key point remains unknown as to how aldehydes are sensed to stimulate phosphorylation of eIF2α in a quantitative manner. In this study, we revealed that the intracellular levels of free histidine were selectively decreased by 50% in hearts exposed to elevated levels of aldehydes. In particular, a sensor of amino acid deficiency, GCN2 (general control nonderepressible-2), which is one of the eIF2・ kinases, was activated. Interestingly, normalization of the intracellular levels of free histidine by feeding a high-histidine diet decreased the phosphorylation levels of GCN2 and eIF2・・ in hearts, resulting in the suppression of ATF4-mediated gene expression and cardioprotection against ischemia-reperfusion injury. An aldehyde, 4-hydroxy-2-nonenal directly reacts histidine to decrease intracellular free histidine levels, culminating in the phosphorylation of eIF2・ in wild-type cells, but not in GCN2^<-/-> cells. Thus, GCN2 senses aldehyde stress in a quantitative manner by monitoring a decline in intracellular free histidine levels. This must be a novel and common scheme as an important sensor of oxidative stress.