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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390228/
• 关键词: 心筋代謝; 抗酸化ストレス応答; レドックス制御; アミノ酸; 酸化ストレス; 虚血再灌流障害; 心不全; アミノ酸代謝; シグナル伝達

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的转基因小鼠对缺血再灌注损伤的心脏保护作用增强。其机制为eIF2α磷酸化下Atf4的选择性上调协调了氨基酸生物合成和抗氧化应激相关基因的表达。然而，一个重要的关键点仍然未知，即醛是如何被感知以定量的方式刺激eIF2α磷酸化的。在这项研究中，我们发现在暴露于高水平醛的心脏中，细胞内游离组氨酸水平选择性地降低了50%。特别是，eIF2激酶之一的氨基酸缺乏传感器GCN2（一般控制非抑制-2）被激活。有趣的是，通过饲喂高组氨酸饮食使细胞内游离组氨酸水平正常化，降低了心脏中GCN2和eIF2的磷酸化水平，从而抑制了atf4介导的基因表达和对缺血再灌注损伤的心脏保护作用。醛，4-羟基-2-壬烯醛直接与组氨酸反应以降低细胞内游离组氨酸水平，最终在野生型细胞中磷酸化eIF2·，但在GCN2^<-/->细胞中没有磷酸化。因此，GCN2通过监测细胞内游离组氨酸水平的下降，以定量的方式感知醛胁迫。这一定是一种新颖而通用的方案，可以作为氧化应激的重要传感器。

项目成果

Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle

• DOI: 10.1016/j.cmet.2011.01.001
• 发表时间: 2011-02-02
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Shimizu, Noriaki;Yoshikawa, Noritada;Tanaka, Hirotoshi
• 通讯作者: Tanaka, Hirotoshi

Mitochondrial biogenesis by hormesis.

通过毒物兴奋作用进行线粒体生物发生。

• 发表时间: 2008
• 期刊: Circulation Research 103
• 作者: Sano M;Fukuda K.
• 通讯作者: Fukuda K.

心筋脂質代謝からアプローチする新たな心不全治療戦略-メタボローム解析に基づく心筋機能制御

从心肌脂质代谢入手的心力衰竭治疗新策略——基于代谢组分析的心肌功能控制

• 发表时间: 2009
• 作者: Usami S;Kishimoto I;Saito Y;Harada M;Kuwahara K;Nakagawa Y;Nakanishi M;Yasuno S;Kangawa K;Nakao K.;Sano M.;桑原宏一郎;佐野元昭
• 通讯作者: 佐野元昭

アンチエイジング医学の基礎と臨床(改訂2版)

抗衰老医学基础与临床实践（修订第2版）

• 发表时间: 2008
• 作者: 細野邦広;高橋宏和;中島淳;佐野元昭
• 通讯作者: 佐野元昭

ATF4-dependent metabolic shift towards Phgdh-mediated serine synthesis enhanced cardioprotection to oxidative stress as a hormetic response to aldehydes.

ATF4 依赖性代谢转变为 Phgdh 介导的丝氨酸合成，作为对醛的激效反应，增强了对氧化应激的心脏保护作用。

• 发表时间: 2008
• 作者: Nishioka Y;et al.;Nozaki Y;Sano M.
• 通讯作者: Sano M.