A role of amino acid metabolism in the oxidative stress response

氨基酸代谢在氧化应激反应中的作用

基本信息

批准号：
20390228
负责人：
SANO Motoaki
金额：
$ 12.15万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

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.

相反，我们发现，长期暴露于醛类可增强暴露于高浓度醛类的转基因小鼠的心脏对缺血再灌注损伤的保护作用，其机制被揭示为在 eIF2α 协调表达的基因组磷酸化下 Atf4 的选择性上调。然而，关于如何感知醛以刺激氨基酸的磷酸化，一个重要的关键点仍然未知。在这项研究中，我们以定量的方式发现，在暴露于醛水平的心脏中，细胞内游离组氨酸的水平选择性地降低了 50%，特别是氨基酸升高缺乏的传感器 GCN2（一般控制非抑制性-）。简单来说，eIF2·激酶之一的eIF2·激酶2)被激活，通过喂食高组氨酸饮食使细胞内游离组氨酸水平正常化，从而降低了eIF2·激酶的磷酸化水平。心脏中的 GCN2 和 eIF2・・，导致 ATF4 介导的基因表达受到抑制，并保护心脏免受缺血再灌注损伤。醛 4-羟基-2-壬烯醛直接与组氨酸反应，降低细胞内游离组氨酸水平，最终导致磷酸化。 eIF2· 在野生型细胞中存在，但在 GCN2^<-/-> 细胞中则不然。因此，GCN2 在 a 中感知醛应激。通过监测细胞内游离组氨酸水平的下降来进行检测，这必定是一种新颖且常见的方案，作为定量氧化应激的重要传感器。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury.

吸入氢气可减少大鼠心肌缺血再灌注损伤模型中的梗塞面积。

DOI：
发表时间：
2008
期刊：
影响因子：
0
作者：
Hayashida K; Sano M; Ohsawa I; Shinmura K; Tamaki K; Kimura K; Endo J; Katayama T; Kawamura A; Kohsaka S; Makino S; Ohta S; Ogawa S; Fukuda K
通讯作者：
Fukuda K

Mitochondrial oxidative stress induces an integrated stress response in the heart.

线粒体氧化应激会引起心脏的综合应激反应。