Elucidation of molecualr mechanism underlying cardiac hibernation by reactive persulfide species

• Project/Area Number: 15K14959
• 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: Motohiro Nishida 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): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 循環器 / 薬理学 / 生理学 / レドックス / 親電子 / イオウ / 活性イオウ / 心臓 / 冬眠化 / 活性酸素 / 心不全

Outline of Final Research Achievements

We utilize oxygen as a source to generate energy. In contrast, oxygen easily converts to more electrophilic substrate (electophile) and electrophile irreversibly modifies intracellular molecules, resulting in the development of diseases. We revealed that intracellular nucleophilic sulfur species (reactive persulfide species) act as chelator of electrophile to eliminate electrophilic modifications in cells. We also identified a key enzyme generating reactive persulfide species, and overexpression of this enzyme in cardiac cells was found to reduce the risk of heart failure in mice.

Research Products

• [Int'l Joint Research] Sabah大学医学部(マレーシア)
• [Int'l Joint Research] Mahidol大学(タイ)
• [Int'l Joint Research] Catholic University of Argentina(アルゼンチン)
• [Int'l Joint Research] NIEHS(米国)
• [Int'l Joint Research] Mahidol University(タイ)
• [Int'l Joint Research] Sabah University(マレーシア)
• [Journal Article] Purinergic P2Y6 receptors: a new therapeutic target of age-dependent hypertension (2017)
  • Author(s): Sunggip C, Nishimura A, Shimoda K, Numaga-Tomita T, Tsuda M, and Nishida M. M
  • Journal Title: Pharmacological Research Volume: 120 Pages: 51-59
  • DOI: 10.1016/j.phrs.2017.03.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts. (2017)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Fujishima A, Oka S, Tsutamoto T, Kinoshita H, Nakao K, Cho K, Inazumi H, Okamoto H, Nishida M, Kato T, Fukushima H, Yamashita JK, Wijnen WJ, Creemers EE, Kangawa K, Minamino N, Nakao K, Kimura T.
  • Journal Title: J Am Heart Assoc. Volume: 6 Issue: 2
  • DOI: 10.1161/jaha.116.003601
  • NAID: 120007100125
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells (2017)
  • Author(s): Nishida M, Nishimura A, Matsunaga T, Motohashi H, Kasamatsu S, Akaike T.
  • Journal Title: Free Radic Biol Med. Volume: 印刷中 Pages: 30033-3
  • DOI: 10.1016/j.freeradbiomed.2017.01.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPC3 participates in angiotensin II type 1 receptor-dependent stress-induced slow increase in intracellular Ca2+ concentration in mouse cardiomyocytes (2017)
  • Author(s): Yamaguchi Y, Iribe G, Kaneko T, Takahashi K, Numaga-Tomita T, Nishida M, Birnbaumer L, Naruse K.
  • Journal Title: J. Physiol. Sci. Volume: 印刷中 Issue: 2 Pages: 1-12
  • DOI: 10.1007/s12576-016-0519-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. (2016)
  • Author(s): Numaga-Tomita T., Kitajima N., Kuroda T., Nishimura A., Miyano K., Yasuda S., Kuwahara K., Sato Y., Ide T., Birnbaumer L., Sumimoto H., Mori Y. and Nishida M.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 39383-39383
  • DOI: 10.1038/srep39383
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling. (2016)
  • Author(s): Kitajima N., Numaga-Tomita T., Watanabe M., Kuroda T., Nishimura A., Miyano K., Yasuda S., Kuwahara K., Sato Y., Ide T., Birnbaumer L., Sumimoto H., Mori Y. and Nishida M
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37701-37701
  • DOI: 10.1038/srep37001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells (2016)
  • Author(s): Unoki T, Abiko Y, Toyama T, Uehara T, Tsuboi K, Nishida M, Kaji T, Kumagai Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28944-28944
  • DOI: 10.1038/srep28944
  • NAID: 120007135346
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of radioiodinated probes to evaluate the biodistribution of a potent TRPC3 inhibitor (2016)
  • Author(s): M. Hagimori, T. Murakami, K. Shimizu, M. Nishida, T. Ohshima, T. Mukai
  • Journal Title: MedChemComm Volume: 7 Issue: 5 Pages: 1003-1006
  • DOI: 10.1039/c6md00023a
  • Peer Reviewed / Open Access
• [Journal Article] Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides (2016)
  • Author(s): Fujii S, Sawa T, Nishida M, Ihara H, Ida T, Motohashi H, Akaike T.
  • Journal Title: Arch Biochem Biophys. Volume: 595 Pages: 140-146
  • DOI: 10.1016/j.abb.2015.11.008
  • Peer Reviewed / Open Access
• [Journal Article] Redox signaling regulated by electrophiles and reactive sulfur species (2016)
  • Author(s): Nishida M, Kumagai Y, Ihara H, Fujii S, Motohashi H, Akaike T.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 58 Issue: 2 Pages: 91-98
  • DOI: 10.3164/jcbn.15-111
  • NAID: 130005132519
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TRPC3 amplifies B cell receptor-induced ERK signaling via protein kinase D-dependent Rap1 activation (2016)
  • Author(s): T. Numaga-Tomita, M. Nishida, J.W. Jr. Putney and Y. Mori
  • Journal Title: Biochem J Volume: 473(2) Issue: 2 Pages: 201-210
  • DOI: 10.1042/bj20150596
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sustained betaAR stimulation mediates cardiac insulin resistance in a PKA-dependent manner (2016)
  • Author(s): S. Mangmool, T. Denkaew, S. Phosri, D. Pinthong, W. Parichatikanond, T. Shimauchi and M. Nishida
  • Journal Title: Mol. Endocrinol. Volume: 30(1) Issue: 1 Pages: 118-132
  • DOI: 10.1210/me.2015-1201
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds (2016)
  • Author(s): S. Sawamura, M. Hatano, Y. Takada, K. Hino, T. Kawamura, J. Tanikawa, H. Nakagawa, H. Hase, A. Nakao, M. Hirano, R. Rotrattanadumrong, S. Kiyonaka, M.X. Mori, M. Nishida, Y. Hu, R. Inoue, R. Nagata and Y. Mori
  • Journal Title: Mol Pharmacol Volume: 89(3) Issue: 3 Pages: 348-363
  • DOI: 10.1124/mol.115.102863
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The purinergic P2Y6 receptor heterodimerizes with the angiotensin AT1 receptor to promote angiotensin II-induced hypertension (2016)
  • Author(s): A. Nishimura, C. Sunggip, H. Tozaki-Saitoh, T. Shimauchi, T. Numaga-Tomita, K. Hirano, T. Ide, J-M. Boeynaems, H. Kurose, M. Tsuda, B. Robaye, K. Inoue and M. Nishida
  • Journal Title: Science Signaling Volume: Jan 19;9(411) Issue: 411
  • DOI: 10.1126/scisignal.aac9187
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Divergent Roles of CAAX Motif-signaled Posttranslational Modifications in the Regulation and Subcellular Localization of Ral GTPases (2015)
  • Author(s): LR Gentry, A. Nishimura, A.D. Cox, T.D. Martin, D. Tsygankov, M. Nishida, T.C. Elston and C.J. Der
  • Journal Title: J Biol Chem. Volume: 290(37) Issue: 37 Pages: 22851-22861
  • DOI: 10.1074/jbc.m115.656710
  • 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
• [Presentation] Myocardial early senescence mediated by mitochondria-cytoskeleton interaction (2016)
  • Author(s): Nishida M
  • Organizer: The 39th Annual Meeting of the Molecular Biology Society of Japan (international symposium)
  • Place of Presentation: Pacifico Yokohama, Yokohama, Kanagawa
  • Year and Date: 2016-12-01
  • Int'l Joint Research
• [Presentation] Regulation of cardiac oxygen remodeling via electrophilic modification of Drp1 (2016)
  • Author(s): Nishida M
  • Organizer: The 89th Annual Meeting of the Japanese Biochemical Society (international symposium)
  • Place of Presentation: Sendai International Conference Center, Sendai, Miyagi
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] TRPC channels in cardiovascular stress resilience (2016)
  • Author(s): Nishida M
  • Organizer: International and Interdisciplinary Symposium 2016 “Towards a New Era of Cardiovascular Research”
  • Place of Presentation: Tokyo Medical and Dental University, Bunkyo-ku, Tokyo
  • Year and Date: 2016-07-11
  • Int'l Joint Research / Invited
• [Presentation] Redox regulation of G proteins in cardiac remodeling (2016)
  • Author(s): Nishida M
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Sendai International Conference Center, Sendai, Miyagi
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] 活性イオウによる心筋のストレス適応・不適応の分子制御 (2016)
  • Author(s): 西田基宏
  • Organizer: 日本獣医学会比較薬理毒性分科会
  • Place of Presentation: 日本大学、神奈川県藤沢市
  • Invited
• [Presentation] Imitation of kinesitherapy by inhibition of TRPC6 channel activities (2015)
  • Author(s): M. Nishida
  • Organizer: International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
  • Place of Presentation: 熊本大学（熊本県熊本市）
  • Year and Date: 2015-10-16
  • Int'l Joint Research / Invited
• [Presentation] Negative regulation of cardiac remodeling by S-polythiolation of G proteins (2015)
  • Author(s): M. Nishida
  • Organizer: 2nd Symposium of SPU Innovative Project for Pharmaceutical Analyses of Covalent Modification in Biomolecule
  • Place of Presentation: 昭和薬科大学（東京都町田市）
  • Year and Date: 2015-08-31
  • Int'l Joint Research / Invited
• [Remarks] 心循環シグナル研究部門
  • URL: http://www.nips.ac.jp/circulation/
• [Remarks] 生理学研究所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 (2015)
  • Inventor(s): 西田基宏、石川達也
  • Industrial Property Rights Holder: 味の素株式会社、自然科学研究機構
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-11-20
  • Overseas