活性硫黄種によるレドックス恒常性維持機構に基づいた新規心不全治療戦略の構築 Establishment of a Novel Therapeutic Strategy for Heart Failure Based on the Mechanism Underlying Maintenance of Redox Homeostasis by Reactive Sulfur Species

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著者

    • 西田 基宏 Nishida Motohiro
    • 自然科学研究機構岡崎統合バイオサイエンスセンター(生理学研究所)心循環シグナル研究部門|総合研究大学院大学生理科学専攻|科学技術振興機構さきがけ「疾患代謝」|九州大学大学院薬学研究院創薬産学官連携講座 Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences|The Graduate University for Advanced Studies (Sokendai)|PRESTO, Japan Science and Technology Agency (JST)|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University
    • 外山 喬士 Toyama Takashi
    • 自然科学研究機構岡崎統合バイオサイエンスセンター(生理学研究所)心循環シグナル研究部門|筑波大学医学医療系環境生物学 Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences|Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba
    • 沼賀(冨田) 拓郎 Numaga-Tomita Takuro
    • 自然科学研究機構岡崎統合バイオサイエンスセンター(生理学研究所)心循環シグナル研究部門|総合研究大学院大学生理科学専攻 Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences|The Graduate University for Advanced Studies (Sokendai)

抄録

  Cardiac redox homeostasis is precisely regulated by reactive oxygen species (ROS) or electrophilic molecules that are formed by ROS reacting with intracellular substrates, and their eliminating systems. We have focused on the role of nitric oxide (NO) generated from inducible NO synthase (iNOS) that is continuously upregulated from early stage of heart failure, and revealed that iNOS-derived NO acts as a protective factor in the early stage of heart failure, whereas it contributes to induction of cardiac early senescence in later stages. The switching mechanism of NO-mediated signaling includes formation of endogenous NO-derived electrophilic byproducts such as 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), which selectively targets an oncogenic small GTPase H-Ras at Cys-184, leading to cardiac cell senescence <i>via</i> covalent modification (<i>S</i>-guanylation) and activation of H-Ras. We also found that hydrogen sulfide-related reactive sulfur species (RSS) function as potent nucleophiles to eliminate electrophilic modification of H-Ras and suppress the onset of chronic heart failure after myocardial infarction. Our results strongly suggest a new concept of redox biology in which suppression of electrophilic irreversible modification of protein cysteine thiols by RSS may be a new therapeutic strategy of cardiovascular diseases.<br>

収録刊行物

  • 薬学雑誌. 乙号

    薬学雑誌. 乙号 134(12), 1239-1243, 2014

    公益社団法人 日本薬学会

各種コード

  • NII論文ID(NAID)
    130004712987
  • NII書誌ID(NCID)
    AN00284903
  • 本文言語コード
    JPN
  • ISSN
    0031-6903
  • NDL 記事登録ID
    025939349
  • NDL 請求記号
    Z19-411
  • データ提供元
    NDL  J-STAGE 
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