2010 Fiscal Year Final Research Report
A role of amino acid metabolism in the oxidative stress response
| 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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| Keywords | 心筋代謝 / 抗酸化ストレス応答 / レドックス制御 |
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| 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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Research Products
(35 results)
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[Journal Article] Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle2011
Author(s)
Shimizu N, Yoshikawa N, Ito. N, Maruyama T, Suzuki Y, Takeda S, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H
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Journal Title
Cell Metab 13(2)
Pages: 170-82
Peer Reviewed
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[Journal Article] The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes2010
Author(s)
Kinouchi K, Ichihara A, Sano M, Sun-Wada GH, Wada Y, Kurauchi-Mito A, Bokuda K, Narita T, Oshima Y, Sakoda M, Tamai Y, Sato H, Fukuda K, Itoh H
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Journal Title
Circ Res. 107(1)
Pages: 30-4
Peer Reviewed
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[Journal Article] 4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway.2010
Author(s)
Zhang Y, Sano M, Shinmura K, Tamaki K, Katsumata Y, Matsuhashi T, Morizane S, Ito H, Hishiki T, Endo J, Zhou H, Yuasa S, Kaneda R, Suematsu M, Fukuda K
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Journal Title
J Mol Cell Cardiol. 49(4)
Pages: 576-86
Peer Reviewed
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[Journal Article] Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart.2009
Author(s)
Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, Matsuhashi T, Katsumata Y, Zhang Y, Ito H, Nagahata Y, Marchitti S, Nishimaki K, Wolf AM, Nakanishi H, Hattori F, Vasiliou V, Adachi T, Ohsawa I, Taguchi R, Hirabayashi Y, Ohta S, Suematsu M, Ogawa S, Fukuda K
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Journal Title
Circ Res. 105(11)
Pages: 1118-27
Peer Reviewed
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[Journal Article] Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism.2009
Author(s)
Yoshikawa N, Nagasaki M, Sano M, Tokudome S, Ueno K, Shimizu N, Imoto S, Miyano S, Suematsu M, Fukuda K, Morimoto C, Tanaka H
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Journal Title
Am J Physiol Endocrinol Metab. 296(6)
Pages: E1363-73
Peer Reviewed
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[Journal Article] Glucocorticoid protects heart from ischemia-reperfusion injury through activation of lipocalin-type prostaglandin D synthase-derived PGD2 biosynthesis.2009
Author(s)
Tokudome S, Sano M, Shinmura K, Matsuhashi T, Morizane S, Moriyama H, Tamaki K, Hayashida K, Nakanishi H, Yoshikawa N, Shimizu N, Endo J, Katayama T, MurataM, Yuasa S, Kaneda R, Tomita K, Eguchi N, Urade Y, Asano K, Utsunomiya Y, Suzuki T, Taguchi R, Tanaka H, Fukuda K
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Journal Title
J Clin Invest. 119(6)
Pages: 1477-88
Peer Reviewed
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[Journal Article] Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury.2008
Author(s)
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
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Journal Title
Biochem Biophys Res Commun. 373(1)
Pages: 30-5
Peer Reviewed
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