Establishment of the molecualr basis underlying regulation of cardiac redox homeostasis by electrophilic signaling and its therapeutic application for heart failure

• Project/Area Number: 25670031
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Okazaki Research Facilities, National Institutes of Natural Sciences
• Principal Investigator: NISHIDA Motohiro 大学共同利用機関法人自然科学研究機構(岡崎共通研究施設), 岡崎統合バイオサイエンスセンター, 教授 (90342641)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 活性酸素 / 硫黄 / 循環 / 心不全 / 活性イオウ / レドックス / 心臓 / 親電子 / 生物系薬学 / 心血管 / Ｇタンパク質 / 翻訳後修飾

Outline of Final Research Achievements

We have reported the possibility that hydrogen sulfide anion (H2S/HS-) protects against chronic heart failure via nucleophilic elimination of endogenous electrophiles in mouse hearts after myocardial infarction. However, it is still obscure whether H2S/HS- acts as a molecular entity of reactive nucleophile in hearts. In this study, we aim to identify the molecular entity of nucleophilic reactive sulfur species (RSS) in hearts and establish an innovative strategy based on the to treat chronic heart failure. We found that proteins containing cysteine persulfide or polysulfide acts as RSS, and accumulation of RSS by taking a polysulfur (garlic)-containing diet dramatically suppresses cardiac risk after myocardial infarction in mice. These results strongly suggest that preservation of RSS in heart will be a novel strategy to reduce cardiac risk.

Research Products

• [Journal Article] Role of 8-nitro-cGMP and its redox regulator in cardiovascular electrophilic signaling (2014)
  • Author(s): Motohiro Nishida, Takashi Toyama, and Takaaki Akaike
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 73 Pages: 10-17
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure. (2014)
  • Author(s): Yamada Y, Kinoshita H, Kuwahara K, Nakagawa Y, Kuwabara Y, Minami T, Yamada C, Shibata J, Nakao K, Cho K, Arai Y, Yasuno S, Nishikimi T, Ueshima K, Kamakura S, Nishida M, Kiyonaka S, Mori Y, Kimura T, Kangawa K, Nakao K.
  • Journal Title: Cardiovasc Res. Volume: 104 Pages: 183-193
  • NAID: 120005619790
  • Peer Reviewed
• [Journal Article] Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species. (2014)
  • Author(s): Nishida M, Toyama T, Kumagai Y, Numaga-Tomita T.
  • Journal Title: Yakugaku Zasshi. Volume: 134 Pages: 1239-1243
  • NAID: 130004712987
  • Acknowledgement Compliant
• [Journal Article] Role of 8-nitro-cGMP and its redox regulation in cardiovascular electrop hilic signaling (2014)
  • Author(s): Nishida M, Toyama T and Akaike T
  • Journal Title: J Mol Cell Cardiol Volume: (In press) Pages: 10-17
  • DOI: 10.1016/j.yjmcc.2014.02.003
  • Peer Reviewed
• [Journal Article] β-arrestin2 in infiltrated macrephages iihibits excessive inflammation aftermyocardial infarction (2013)
  • Author(s): Watari K, Nakaya M, Nishida M, Kim KM, Kurose H
  • Journal Title: PLOSONE Volume: 8 Issue: 7 Pages: e68351-e68351
  • DOI: 10.1371/journal.pone.0068351
  • Peer Reviewed
• [Journal Article] GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance (2013)
  • Author(s): Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H
  • Journal Title: Nature Commun Volume: 4 Issue: 1 Pages: 1532-1532
  • DOI: 10.1038/ncomms2540
  • Peer Reviewed
• [Journal Article] Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice. (2013)
  • Author(s): Nishida M, Ishikawa T, Saiki S, Sunggip C, Aritomi S, Harada E, Kuwahara K, Hirano K, Mori Y, Kim-Mitsuyama S
  • Journal Title: Biochem Biophys Res Commun. Volume: 434 Issue: 2 Pages: 210-216
  • DOI: 10.1016/j.bbrc.2013.03.040
  • Peer Reviewed
• [Journal Article] Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels. (2013)
  • Author(s): Chen W, Oberwinkler H, Werner F, Gaßner B, Nakagawa H, Feil R, Hofmann F, Schlossmann J, Dietrich A, Gudermann T, Nishida M, Del Galdo S, Wieland T, Kuhn M.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 33 Issue: 9 Pages: 2121-2129
  • DOI: 10.1161/atvbaha.113.001974
  • Peer Reviewed
• [Journal Article] Formation, signaling functions, and metabolisms of nitrated cyclic nucleotide. (2013)
  • Author(s): Sawa T, Ihara H, Ida T, Fujii S, Nishida M and Akaike T.
  • Journal Title: Nitric Oxide Volume: 34 Pages: 10-18
  • DOI: 10.1016/j.niox.2013.04.004
  • Peer Reviewed
• [Journal Article] Regulation of redox signaling by an electrophilic cyclic nucleotide. (2013)
  • Author(s): Akaike T, Nishida M and Fujii S.
  • Journal Title: J. Biochem. Volume: 153 Issue: 2 Pages: 131-138
  • DOI: 10.1093/jb/mvs145
  • Peer Reviewed
• [Journal Article] Redox control of cardiovascular homeostasis by Angiotensin II. (2013)
  • Author(s): Sunggip C, Kitajima N & Nishida M
  • Journal Title: Curr. Pharm. Des. Volume: 19 Pages: 3022-3032
  • Peer Reviewed
• [Journal Article] 酸化ストレスによるレドックス恒常性異常と心筋リモデリング (2013)
  • Author(s): 西田基宏
  • Journal Title: 医学のあゆみ Volume: 247 Pages: 875-878
• [Journal Article] 硫化水素アニオンによるレドックス恒常性制御とその臨床応用 (2013)
  • Author(s): 西田基宏，澤智裕
  • Journal Title: 生化学 Volume: 85 Pages: 996-999
• [Presentation] Covalent modification of H-Ras by nitric oxide-derived reactive species underlies development of chronic heart failure in mice. (2014)
  • Author(s): Motohiro Nishida
  • Organizer: 17th World Congress of Basic & Clinical Pharmacology (WCP2014)
  • Place of Presentation: ケープタウン、南アフリカ
  • Year and Date: 2014-07-13 – 2014-07-18
  • Invited
• [Presentation] Activation mechanism of H-Ras GTPase via electrophilic modification of Cys-184. (2014)
  • Author(s): Nishida M
  • Organizer: The 231st IMEG seminars & Minisymposium. Recent advances and future directions in high-speed AFM imaging of ATP/GTP-driven molecular machinery
  • Place of Presentation: 熊本大学発生医学研究所（熊本県）
  • Invited
• [Presentation] G蛋白質の酸化修飾による心血管リモデリング制御 (2014)
  • Author(s): 西田基宏
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター（宮城県）
• [Presentation] 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 (2014)
  • Author(s): 西田基宏、外山喬士、熊谷嘉人、冨田拓郎
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市鶴屋百貨店東館（熊本県）
• [Presentation] 含硫機能性食品を用いた心不全治療 (2013)
  • Author(s): 外山喬士、西田基宏
  • Organizer: 第23回日本循環薬理学会
  • Place of Presentation: 福岡大学メディカルホール（福岡県）
• [Remarks] 心循環シグナル研究部門
  • URL: http://www.nips.ac.jp/circulation
• [Patent(Industrial Property Rights)] Drp1重合阻害剤 (2014)
  • Inventor(s): 西田基宏、石川達也
  • Industrial Property Rights Holder: 西田基宏、石川達也
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-236941
  • Filing Date: 2014-11-24