| Project/Area Number |
20390228
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Keio University |
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Principal Investigator |
SANO Motoaki Keio University, 医学部, 講師 (30265798)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
Fiscal Year 2010: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2008: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
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| Keywords | 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 |
|---|
| Research Abstract |
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.
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