Functional relationship between metabolism of sulfur-containing amino acids and cardioprotection from ischemia-reperfusion injury

• Project/Area Number: 25460072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Keio University
• Principal Investigator: Ishii Isao 慶應義塾大学, 薬学部, 准教授 (90292953)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ホモシステイン / 硫化水素 / 心血管病 / 危険因子 / 活性イオウ分子 / 虚血再灌流障害 / 硫黄転移経路 / システイン / トランススルフレーション / 遺伝子改変マウス / 心筋保護 / 絶食 / 活性イオウ分子種 / 虚血プレコンディショニング / 酸化障害 / リモデリング / 活性硫黄分子種

Outline of Final Research Achievements

Elevated levels of homocysteine in plasma are considered as a risk factor for cardiovascular diseases; however, how homocysteine works are still largely unclear. We aim to reveal its molecular mechanisms through investigating genetically engineered mice lacking CBS and CTH, two trans-sulfuration enzymes essential for cysteine biosynthesis from homocysteine as well as for endogenous production of bioactive (cell-protective) hydrogen sulfide production. In this project, we obtained experimental evidence as a novel mechanism of homocysteine actions that homocysteine directly captures a hydrogen sulfide anion (by forming homocysteine persulfide), thereby counteracting their biological effects. Our results suggest that the regulation of hydrogen sulfide signaling may contribute to the amelioration of homocysteine-related cardiovascular diseases.

Research Products

• [Int'l Joint Research] Scripps Institute(米国)
• [Int'l Joint Research] Friedrich-Alexander University(ドイツ)
• [Int'l Joint Research] University of Giessen(ドイツ)
• [Int'l Joint Research] Sonoma State University(米国)
• [Journal Article] Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet-Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice (2016)
  • Author(s): Kitada Y, Kajita K, Taguchi K, Mori I, Yamauchi M, Ikeda T, Kawashima M, Asano M, Kajita T, Ishizuka T, Banno Y, Kojima I, Chun J, Kamata S, Ishii I, Morita H.
  • Journal Title: Endocrinology Volume: 印刷中 Issue: 5 Pages: 1839-1851
  • DOI: 10.1210/en.2015-1768
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. (2016)
  • Author(s): Wedmann R, Onderka C, Wei S, Szijarto IA, Miljkovic JL, Mitrovic A, Lange M, Savitsky S, Yadav PK, Torregrossa R, Harrer EG, Harrer T, Ishii I, Gollasch M, Wood ME, Galardon E, Xian M, Whiteman M, Banerjee R, Filipovic MR.
  • Journal Title: Chemical Science Volume: 7 Issue: 5 Pages: 3414-3426
  • DOI: 10.1039/c5sc04818d
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2016)
  • Author(s): Klionsky DJ., Abdelmohsen K., Abe A., Abedin MJ.,Inomata M., et al.
  • Journal Title: Autophagy Volume: 12(1) Issue: 1 Pages: 1-222
  • DOI: 10.1080/15548627.2015.1100356
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice (2015)
  • Author(s): Ishii I, Kamata S, Hagiya Y, Abiko Y, Kasahara T, Kumagai Y.
  • Journal Title: The Journal of Toxicological Sciences Volume: 40 Issue: 6 Pages: 837-841
  • DOI: 10.2131/jts.40.837
  • NAID: 130005108870
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Formation of Sulfur Adducts of N-Acetyl-p-benzoquinoneimine, an Electrophilic Metabolite of Acetaminophen in Vivo: Participation of Reactive Persulfides. (2015)
  • Author(s): Abiko Y., Ishii I., Kamata S., Tsuchiya Y., Watanabe Y., Ihara H., Akaike T., Kumagai Y.
  • Journal Title: Chem. Res. Toxicol. Volume: 28 Issue: 9 Pages: 1796-1802
  • DOI: 10.1021/acs.chemrestox.5b00245
  • Peer Reviewed / Open Access
• [Journal Article] The H2S-generating enzymes cystathionine beta-synthase and cystathionine gamma-lyase play a role in vascular development during normal lung alveolarization. (2015)
  • Author(s): Madurga A, Golec A, Pozarska A, Ishii I, Mizikova I, Nardiello C, Vadasz I, Herold S, Mayer K, Reichenberger F, Fehrenbach H, Seeger W, Morty RE.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 309 Issue: 7 Pages: L710-L724
  • DOI: 10.1152/ajplung.00134.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 2D DIGE proteomic analysis highlights delayed postnatal repression of α-fetoprotein expression in homocystinuria model mice. (2015)
  • Author(s): Kamata S, Akahoshi N, Ishii I.
  • Journal Title: FEBS Open Bio Volume: 5 Issue: 1 Pages: 535-541
  • DOI: 10.1016/j.fob.2015.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Differential adaptive responses to 1- or 2-day fasting in various mouse tissues revealed by quantitative PCR analysis. (2015)
  • Author(s): Yamamoto J, Kamata S, Miura A, Nagata T, Kainuma R, Ishii I.
  • Journal Title: FEBS Open Bio. Volume: 5 Issue: 1 Pages: 357-368
  • DOI: 10.1016/j.fob.2015.04.012
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of reactive persulfides in biological bismethylmercury sulfide formation. (2015)
  • Author(s): Abiko Y, Yoshida E, Ishii I, Fukuto JM, Akaike T, Kumagai Y.
  • Journal Title: Chemical Research in Toxicology. Volume: 28 Issue: 6 Pages: 1301-1306
  • DOI: 10.1021/acs.chemrestox.5b00101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive sulfur species-mediated activation of the Keap1-Nrf2 pathway by 1,2-napthoquinone through sulfenic acids formation under oxidative stress. (2015)
  • Author(s): Shinkai Y, Abiko Y, Ida T, Miura T, Kakehashi H, Ishii I, Nishida M, Sawa T, Akaike T, Kumagai Y.
  • Journal Title: Chem Res Toxicol. Volume: 印刷中 Issue: 5 Pages: 838-847
  • DOI: 10.1021/tx500416y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions. (2015)
  • Author(s): Nakano S, Ishii I, Shinmura K, Tamaki K, Hishiki T, Akahoshi N, Ida T, Nakanishi T, Kamata S, Kumagai Y, Akaike T, Fukuda K, Sano M, Suematsu M.
  • Journal Title: J Mol Med (Berl). Volume: 印刷中 Issue: 8 Pages: 879-889
  • DOI: 10.1007/s00109-015-1271-5
  • Peer Reviewed / Open Access
• [Journal Article] Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia/reperfusion injury. (2015)
  • Author(s): Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 印刷中 Issue: 8 Pages: H894-H903
  • DOI: 10.1152/ajpheart.00333.2014
  • Peer Reviewed / Open Access
• [Journal Article] Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice. (2015)
  • Author(s): Hagiya Y, Kamata S, Mitsuoka S, Okada N, Yoshida S, Yamamoto J, Ohkubo R, Abiko Y, Yamada H, Akahoshi N, Kasahara T, Kumagai Y, Ishii I.
  • Journal Title: Toxicol Appl Pharmacol. Volume: 282 Issue: 2 Pages: 195-206
  • DOI: 10.1016/j.taap.2014.11.015
  • Peer Reviewed
• [Journal Article] RSSの生合成系とタンパク質機能制御 (2015)
  • Author(s): 渡邊泰男、石井功、蕨栄治
  • Journal Title: 細胞工学 Volume: 34 Pages: 372-376
• [Journal Article] Neutral aminoaciduria in cystathionine beta-synthase-deficient mice, an animal model of homocystinuria. (2014)
  • Author(s): Akahoshi N, Kamata S, Kubota M, Hishiki T, Nagahata Y, Matsuura T, Yamazaki C, Yoshida Y, Yamada H, Ishizaki Y, Suematsu M, Kasahara T, Ishii I
  • Journal Title: Am J Physiol Renal Physiol Volume: なし
  • Peer Reviewed
• [Journal Article] Dietary deprivation of each essential amino acid induces differential systemic adaptive responses in mice. (2014)
  • Author(s): Kamata S, Yamamoto J, Kamijo K, Ochiai T, Morita T, Yoshitomi Y, Hagiya Y, Kubota M, Ohkubo R, Kawaguchi M, Himi T, Kasahara T, Ishii I.
  • Journal Title: Mol Nutr Food Res. Volume: 58 Issue: 6 Pages: 1309-1321
  • DOI: 10.1002/mnfr.201300758
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes Biochem (2013)
  • Author(s): Okamoto M, Yamaoka M, Takei M, Ando T, Taniguchi S, Ishii I, Tohya K, Ishizaki T, Niki I, Kimura T
  • Journal Title: Biophys. Res. Commun Volume: 442 Issue: 3-4 Pages: 227-233
  • DOI: 10.1016/j.bbrc.2013.11.023
  • Peer Reviewed
• [Journal Article] The effect of cse gene deletion in caerulein-induced acute pancreatitis in the mouse. (2013)
  • Author(s): Ang A, Rivers J, Hedge A, Ishii I, Bhatia M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 305
  • Peer Reviewed
• [Journal Article] ホモシステイン血症再考 (2013)
  • Author(s): 石井功
  • Journal Title: 生化学 Volume: 85 Pages: 1067-1071
  • Peer Reviewed
• [Presentation] H2S and homocysteine; new insights from two hyperhomocysteinemic mutant mouse strains that lack H2S-generating enzymes. (2016)
  • Author(s): Ishii I
  • Organizer: 95th Annual Meeting of the German Physiological Society
  • Place of Presentation: Lubeck (Germany)
  • Year and Date: 2016-03-05
  • Int'l Joint Research / Invited
• [Presentation] 心虚血再灌流障害におけるホモシステインの新規作用機序 (2015)
  • Author(s): 石井 功、中埜 信太郎、新村 健、玉城 香代子、菱木 貴子、赤星 軌征、井田 智章、中西 豪、鎌田 祥太郎、熊谷 嘉人、赤池 孝章、福田 恵一、佐野 元昭、末松 誠
  • Organizer: 第88回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド (兵庫県神戸市)
  • Year and Date: 2015-12-04
• [Presentation] 絶食によるマウス臓器タンパク質リモデリングの網羅的プロテオーム解析 (2015)
  • Author(s): 鎌田 祥太郎、山本 隼也、海沼 亮、大谷 遥香、戸坂 優花、笠原 忠、石井 功
  • Organizer: 第88回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド (兵庫県神戸市)
  • Year and Date: 2015-12-03
• [Presentation] 短期絶食によるマウス全身性応答１（臓器別遺伝子発現変化） (2015)
  • Author(s): 鎌田 祥太郎、山本 隼也、三浦 あす美、長田 知子、海沼 亮、石井 功
  • Organizer: 第59回日本薬学会関東支部大会
  • Place of Presentation: 日本大学薬学部 (千葉県船橋市)
  • Year and Date: 2015-09-12
• [Presentation] 短期絶食によるマウス全身性応答２（臓器別タンパク質発現変化） (2015)
  • Author(s): 大谷 遥香、山本 隼也、戸坂 優花、鎌田 祥太郎、石井 功
  • Organizer: 第59回日本薬学会関東支部大会
  • Place of Presentation: 日本大学薬学部 (千葉県船橋市)
  • Year and Date: 2015-09-12
• [Presentation] 食餌誘導性高ホモシステイン血症感受性マウスの解析 (2015)
  • Author(s): 戸坂 優花、大谷 遥香、三浦 あす美、長田 知子、鎌田 祥太郎、石井 功
  • Organizer: 第59回日本薬学会関東支部大会
  • Place of Presentation: 日本大学薬学部 (千葉県船橋市)
  • Year and Date: 2015-09-12
• [Presentation] システイン・活性イオウ分子産生酵素CSEのアセトアミノフェン肝障害における保護的役割 (2015)
  • Author(s): 石井 功、鎌田 祥太郎、我孫子 ユミ、熊谷 嘉人
  • Organizer: 第42回日本毒性学会学術年会
  • Place of Presentation: 石川県立音楽堂 (石川県金沢市)
  • Year and Date: 2015-06-30
  • Invited
• [Presentation] Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion (2015)
  • Author(s): 石井 功、中埜 信太郎、新村 健、玉城 香代子、菱木 貴子、赤星 軌征、井田 智章、中西 豪、鎌田 祥太郎、熊谷 嘉人、赤池 孝章、福田 恵一、佐野 元昭、末松 誠
  • Organizer: 日本薬学会生物系薬学部会主催 第16回Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 長井記念ホール (東京都渋谷区)
  • Year and Date: 2015-06-13
• [Presentation] 高ホモシステイン血症マウスにおける血中α-fetoprotein蓄積 (2015)
  • Author(s): 鎌田 祥太郎、赤星 軌征、石井 功
  • Organizer: 日本薬学会生物系薬学部会主催 第16回Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 長井記念ホール (東京都渋谷区)
  • Year and Date: 2015-06-13
• [Presentation] Adaptive responses against essential amino acid deficiency in mice (2014)
  • Author(s): 鎌田祥太郎、山本隼也、上條健太、落合崇人、森田珠子、吉冨友里香、萩谷至史、久保田将史、大久保里香、笠原忠、石井功
  • Organizer: 日本アミノ酸学会第8回学術大会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-09
• [Presentation] アセトアミノフェン肝障害に対するトランススルフレーション酵素の保護的役割 (2014)
  • Author(s): 石井功、萩谷至史、鎌田祥太郎、光岡紗野、吉田早織、山本隼也、大久保里佳、笠原忠
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-18
• [Presentation] 各必須アミノ酸欠失餌により異なるマウスの全身性適応応答 (2014)
  • Author(s): 鎌田祥太郎、山本隼也、上條健太、落合崇人、森田珠子、吉冨友里香、萩谷至史、久保田将史、大久保里香、笠原忠、石井功
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-18
• [Presentation] 絶食によるマウス各臓器の適応応答とリモデリング (2014)
  • Author(s): 山本隼也、鎌田祥太郎、笠原忠、石井功
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-18
• [Presentation] Neutral aminoaciduria in cystathionine beta-synthase-deficient mice, an animal model of homocystinuria (2014)
  • Author(s): 赤星軌征、鎌田祥太郎、久保田将史、菱木貴子、長畑善子、松浦友美、山崎千穂、吉田由香、山田秀典、石﨑泰樹、末松誠、笠原忠、石井功
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-18
• [Presentation] アセトアミノフェン肝障害におけるタンパク質発現変化のProteome解析 (2014)
  • Author(s): 岡田憲彦、山本隼也、鎌田祥太郎、萩谷至史、笠原忠、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] 食餌アミノ酸センシングによる摂食抑制 (2014)
  • Author(s): 軽部勝仁、三浦あす美、長田知子、鎌田祥太郎、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] Cys生合成酵素欠損マウスにおける肝GSH生合成律速酵素の活性化 (2014)
  • Author(s): 光岡紗野、吉田早織、大久保里香、山本隼也、鎌田祥太郎、萩谷至史、笠原忠、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] 食餌誘導性高ホモシステイン血症マウスの解析 (2014)
  • Author(s): 三浦あす美、長田知子、山本隼也、鎌田祥太郎、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] 非必須アミノ酸欠乏によるマウス血中アミノ酸濃度変化 (2014)
  • Author(s): 長田知子、三浦あす美、山本隼也、鎌田祥太郎、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] 3T3-L1脂肪前駆細胞の脂肪分化に対するホモシステインの効果 (2014)
  • Author(s): 菅澤智秋、鎌田祥太郎、石井功
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
• [Presentation] 心虚血再灌流障害におけるホモシステインと硫化水素の拮抗作用 (2014)
  • Author(s): 石井功
  • Organizer: 第14回日本NO学会学術集会
  • Place of Presentation: 佐賀
  • Year and Date: 2014-05-17
  • Invited
• [Presentation] 高ホモシステイン血症モデルマウスの血漿プロテオーム解析 (2013)
  • Author(s): 鎌田祥太郎, 赤星軌征, 吉川紗弓, 笠原忠, 石井功
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] アセトアミノフェン肝障害増悪化の遺伝的素因としてのシステイン生合成酵素欠損 (2013)
  • Author(s): 萩谷至史, 鎌田祥太郎, 山本隼也, 吉田早織, 笠原忠, 石井功
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] アセトアミノフェン肝障害におけるGlutamate-Cysteine Ligaseの役割 (2013)
  • Author(s): 吉田早織, 萩谷至史, 鎌田祥太郎, 大久保里佳, 笠原忠, 石井功
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
• [Presentation] ホモシスチン尿症モデルマウス肝臓の2D-DIGEプロテオーム解析 (2013)
  • Author(s): 吉川紗弓, 鎌田祥太郎, 山本隼也, 大久保里佳, 吉田早織, 笠原忠, 石井功
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
• [Presentation] アミノ酸欠乏餌投与によるマウス体重変化と血中アミノ酸濃度変化 (2013)
  • Author(s): 久保田将史, 吉田早織, 吉川紗弓, 山本隼也, 大久保里佳, 鎌田祥太郎, 萩谷至史, 笠原忠, 石井功
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京