Identification of novel factor in hereditary sinus bradycardia and its application to preventive medicine

• Project/Area Number: 15K09111
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Satoru Yamazaki 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70348796)
• Co-Investigator(Kenkyū-buntansha): 北風 政史 国立研究開発法人国立循環器病研究センター, 研究開発基盤センター, 部長 (20294069)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 臨床遺伝 / 洞性徐脈 / ゲノム / 循環器 / 刺激伝導組織 / 刺激伝道細胞 / 刺激伝導細胞

Outline of Final Research Achievements

Normal heart rate and rhythm are essential for proper heart function. As disorders of impulse generation and/or propagation in the cardiac conduction system culminate in symptomatic, life-threatening bradyarrhythmias, the ion channels responsible for these phenomena represent promising therapeutic targets. We describe a family affected with hereditary sinus bradycardia. Genetic analysis revealed a novel mutation in KCNJ3, which encodes a subunit of the acetylcholine-activated potassium channel (IKACh channel). The mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of G protein-coupled receptor stimulation. The selective IKACh channel blocker NIP-151 repressed the current increase and improved all bradyarrhythmia phenotypes in zebrafish harbouring the mutation. We thus identified the KCNJ3 mutation as responsible for these bradyarrhythmias and propose that selective IKACh channel blockers may be a valuable therapeutic approach.

Academic Significance and Societal Importance of the Research Achievements

遺伝性徐脈性不整脈の新たな原因として、IKAChチャネルの新規遺伝子変異を同定し、本チャネルの異常活性化が徐脈性不整脈の原因となることを見出した。本チャネルの選択的阻害薬は異常活性化を示す変異型チャネルに対しても高い阻害活性を示し、同チャネル変異を導入した疾患モデル動物においても有効性を示したことから、徐脈性不整脈に対する新規の分子標的治療薬になり得ることが示唆された

Research Products

• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail Volume: 6 Issue: 2 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats. (2019)
  • Author(s): Nakajima Y, Ito S, Asakura M, Min KD, Fu HY, Imazu M, Hitsumoto T, Takahama H, Shindo K, Fukuda H, Yamazaki S, Asanuma H, Kitakaze M.
  • Journal Title: J Molecular and Cellular Cardiology Volume: 129 Pages: 257-265
  • DOI: 10.1016/j.yjmcc.2019.03.009
  • Peer Reviewed
• [Journal Article] Cartilage Intermediate Layer Protein 1 Suppresses TGF-β Signaling in Cardiac Fibroblasts (2017)
  • Author(s): Kazuhiro Shindo, Masanori Asakura, Kyung-Duk Min, Shin Ito, Hai Ying Fu, Satoru Yamazaki, Ayako Takahashi, Miki Imazu, Hiroki Fukuda, Yuri Nakajima, Hiroshi Asanuma, Tetsuo Minamino, Seiji Takashima, Naoto Minamino, Naoki Mochizuki, Masafumi Kitakaze
  • Journal Title: International Journal of Gerontology Volume: 11 Issue: 2 Pages: 67-74
  • DOI: 10.1016/j.ijge.2017.01.002
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy. (2016)
  • Author(s): Ito S, Asakura M, Liao Y, Min KD, Takahashi A, Shindo K, Yamazaki S, Tsukamoto O, Asanuma H, Mogi M, Horiuchi M, Asano Y, Sanada S, Minamino T, Takashima S, Mochizuki N, Kitakaze M.
  • Journal Title: J Am Heart Assoc. Volume: 5 Issue: 7
  • DOI: 10.1161/jaha.116.003521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA. (2016)
  • Author(s): Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28592-28592
  • DOI: 10.1038/srep28592
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Higdla is a oositive regulaator of cytochrome c oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc. Nat. Acad. Sci. U.S.A. Volume: 112 Issue: 5 Pages: 1553-1558
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access
• [Journal Article] Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5. (2015)
  • Author(s): Yan Y, Tsukamoto O, Nakano A, Kato H, Kioka H, Ito N, Higo S, Yamazaki S, Shintani Y, Matsuoka K, Liao Y, Asanuma H, Asakura M, Takafuji K, Minamino T, Asano Y, Kitakaze M, Takashima S.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6137-6137
  • DOI: 10.1038/ncomms7137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An interaction between GLP-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia/reperfusion injury. (2015)
  • Author(s): Ihara M, Asanuma H, Yamazaki S, Kato H, Asano Y, Shinozaki Y, Mori H, Minamino T, Asakura M, Sugimachi M, Mochizuki N, Kitakaze M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: in press Issue: 10 Pages: 1287-1297
  • DOI: 10.1152/ajpheart.00835.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure (2015)
  • Author(s): Takahashi A, Ihara M, Yamazaki S(○), Asanuma H, Asakura M, Kitakaze M
  • Journal Title: International Heart Journal Volume: 56 Issue: 4 Pages: 372-376
  • DOI: 10.1536/ihj.15-028
  • NAID: 130005087570
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213. (2015)
  • Author(s): Kotani Y, Morito D, Yamazaki S, Ogino K, Kawakami K, Takashima S, Hirata H, Nagata K.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 16161-16161
  • DOI: 10.1038/srep16161
  • Peer Reviewed / Open Access
• [Presentation] 家族性洞結節および心房徐脈性不整脈における治療標的を提供するアセチルコリン活性化カリウムチャネルにおける病原性突然変異 (2018)
  • Author(s): 山崎 悟、山田憲明、朝野仁裕、北風 政史、高島 成二
  • Organizer: 第95回 日本生理学会大会
  • Invited
• [Presentation] DPP4 阻害薬alogliptin は、アデノシン依存性のメカニズムを介して、虚血/ 再潅流障害を抑制する (2017)
  • Author(s): 山﨑悟、伊原まどか、浅沼博司、北風政史
  • Organizer: 第38回日本循環制御医学会総会・学術集会
• [Presentation] Cardiac microdialysis enables us to monitor myocardial interstitial microRNA levels in an in-vivo beating rat heart during ischaemia/reperfusion (2017)
  • Author(s): S. Shimizu, S. Yamazaki, T. Akiyama, T. Kawada, J.T. Pearson,T. Shishido, M. Sugimachi
  • Organizer: ESC Congress2017
  • Int'l Joint Research
• [Presentation] 再灌流は、虚血心筋での血管内皮細胞特異的microRNA 分泌を亢進する (2017)
  • Author(s): 清水秀二、山崎 悟、川田 徹、秋山 剛、羽山陽介、James T Pearson、宍戸稔聡、杉町勝
  • Organizer: 第110回 日本生理学会近畿生理学談話会
• [Presentation] エクソーム解析基盤を用いた日本人変異解析における解析手法の検証と可視化 (2017)
  • Author(s): 小林 香織、今井 敦子、山崎 悟,、菊地 正隆,、足尾 勉,、上條 憲一,、松村 泰志、中谷 明弘
  • Organizer: 生命科学系学会合同年次大会
• [Presentation] A truncation mutation in gene encoding cardiac specific kinase X causes dilated cardiomyopathy (2016)
  • Author(s): T. Konno, Hodatsu A, Seguchi O, Yamazaki S(○), Imai A, Uyama Y, Tsukamoto O, Asano Y, Takashima S, Yamagishi, M
  • Organizer: 日本心不全学会大会
  • Place of Presentation: 北海道（札幌）
  • Year and Date: 2016-10-07
• [Presentation] Kir3.1 Channel Mutation, a Novel Therapeutic Target for Familial Sinus Bradycardia and Atrial Fibrillation (2016)
  • Author(s): Noriaki Yamada, Yoshihiro Asano, Tetsuo Minamino, Satoru Yamazaki(○), Seiko Ono, Norio Hashimoto, Toru Yamashita, Minoru Horie, Yoshihisa Kurachi, Issei Komuro, Masafumi Kitakaze, Yasushi Sakata, Seiji Takashima
  • Organizer: 日本循環器学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] AAA+ATPase/ユビキチンリガーゼタンパク質 Mysterin/RNF213 による zebrafish の発生制御. (2015)
  • Author(s): 小谷 友理、森戸大介、山崎 悟(○)、荻野一豊、高島成二、平田晋三、永田和宏
  • Organizer: 日本細胞生物学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-30