Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity

• Project/Area Number: 17K09575
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Ohno Mikiko 滋賀医科大学, 医学部, 准教授 (10583198)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 洞房結節自動能 / メタロプロテアーゼ / 洞不全症候群 / イオンチャネル / 酵素活性 / プロテアーゼ / 転写制御 / 循環器 / 洞房結節

Outline of Final Research Achievements

We have shown that NRDC, a multifunctional protease, controls heart rate by transcriptional regulation of HCN ion-channels responsible for cardiac sinus node automaticity. We specifically demonstrated that NRDC regulates gene expression of these ion channels involved in sinus automaticity by ChIP method using anti-NRDC antibody. Moreover, bradycardia was also shown in atrial (sinoatrial node) specific NRDC-deficient mice (Sln-Nrdc-KO), and expression levels of HCN ion channels were also reduced in Sln-Nrdc knockout hearts. In addition, we generated and analyzed the enzyme-activity-deficient mutant NRDC knock-in mice.

Academic Significance and Societal Importance of the Research Achievements

NRDCの生体における機能はこれまで全く不明であったが、NRDC-/-における研究成果から、NRDCが心拍数、血圧、体温調節などの恒常性維持に重要な役割を持つことが示唆された。一方、NRDCは全身に広く発現するので、NRDC-/-の表現型が一次的かどうかを判断するには困難を伴う。そこで、最近作製した臓器特異的NRDC欠損マウスや酵素活性欠失型変異NRDCマウスの解析を行い、心拍数調節のメカニズムの解明の足掛かりとした。これらの成果を今後発展させることで、ヒトにおける遺伝性洞不全症候群の原因解明やNRDCの酵素活性中心をターゲットとした創薬開発の基盤に役立てることができると考えられた。

Research Products

• [Journal Article] Response to Letter of Stephenson et al.: Nardilysin: A potential biomarker for the early diagnosis of acute coronary syndrome (2019)
  • Author(s): Ohno M, Chen PM, Kimura T, Nishi E.
  • Journal Title: International Journal of Cardiology Volume: 277 Pages: 249-249
  • DOI: 10.1016/j.ijcard.2018.10.022
  • Peer Reviewed
• [Journal Article] Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection (2019)
  • Author(s): Yoh T, Hatano E, Kasai Y, Fujii H, Nishi K, Toriguchi K, Sueoka H, Ohno M, Seo S, Iwaisako K, Taura K, Yamaguchi R, Kurokawa M, Fujimoto J, Kimura T, Uemoto S, and Nishi E.
  • Journal Title: Clinical Cancer Research Volume: 25(2) Pages: 619-628
  • DOI: 10.1158/1078-0432.ccr-18-0124
  • Peer Reviewed / Open Access
• [Journal Article] Reply: Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome. (2018)
  • Author(s): Chen PM, Ohno M, Kimura T, Nishi E.
  • Journal Title: International Journal of Cardiology Volume: 265 Pages: 236-236
  • DOI: 10.1016/j.ijcard.2018.04.056
  • Peer Reviewed
• [Journal Article] Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production. (2018)
  • Author(s): Ito Y, Nakamura S, Sugimoto N, Shigemori T, Kato Y, Ohno M, Sakuma S, Ito K, Kumon H, Hirose H, Okamoto H, Nogawa M, Iwasaki M, Kihara S, Fujio K, Matsumoto T, Higashi N, Hashimoto K, Sawaguchi A, Harimoto KI, Nakagawa M, Yamamoto T, Handa M, Watanabe N.
  • Journal Title: Cell Volume: 174(3) Issue: 3 Pages: 636-648
  • DOI: 10.1016/j.cell.2018.06.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation. (2018)
  • Author(s): Kanda K, Sakamoto J, Matsumoto Y, Ikuta K, Goto N, Morita Y, Ohno M, Nishi K, Eto K, Kimura Y, Nakanishi Y, Ikegami K, Yoshikawa T, Fukuda A, Kawada K, Sakai Y, Ito A, Yoshida M, Kimura T, Chiba T, Nishi E, Seno H.
  • Journal Title: JCI insight Volume: 3 Issue: 8 Pages: 1-15
  • DOI: 10.1172/jci.insight.91316
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of serum levels of antibodies against MMP1, CBX1, and CBX5 with transient ischemic attack and cerebral infarction (2017)
  • Author(s): Wang H,Zhang X-M,Tomiyoshi G,Nakamura R,Shinmen N,Kuroda H,Kimura R,Mine S,Kamitsukasa I,Wada T,Aotsuka A,Yoshida Y,Kobayashi E,Matsutani T,Iwadate Y,Sugimoto K,Mori M,Uzawa A,Muto M,Kuwabara S,Takemoto M,Kobayashi K,Kawamura H,Ishibashi R,Yokote K,Ohno M,
  • Journal Title: Oncotarget Volume: 9 Pages: 5600-5613
  • DOI: 10.18632/oncotarget.23789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion (2017)
  • Author(s): Fujii Takayuki、Nishi Eiichiro、Ito Hiromu、Yoshitomi Hiroyuki、Furu Moritoshi、Okabe Namiko、Ohno Mikiko、Nishi Kiyoto、Morita Yusuke、Morita Yugo、Azukizawa Masayuki、Okahata Akinori、Tomizawa Takuya、Kimura Takeshi、Matsuda Shuichi
  • Journal Title: RMD Open. Volume: 3
  • DOI: 10.1136/rmdopen-2017-000436
  • NAID: 120006325113
  • Peer Reviewed / Open Access
• [Journal Article] Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3 (2017)
  • Author(s): Kasai Y, Toriguchi K, *Hatano E, Nishi K, Ohno M, Yoh T, Fukuyaman K, Nishio T, Okuno M, Iwaisako K, Seo S, Taura K, Kurokawa M, Kunichika M, Uemoto S, *Nishi E
  • Journal Title: Cancer Sci Volume: 108 Pages: 910-17
  • DOI: 10.1111/cas.13204
  • NAID: 120006333898
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome (2017)
  • Author(s): Chen Po-Min、Ohno Mikiko、Hiwasa Takaki、Nishi Kiyoto、Saijo Sayaka、Sakamoto Jiro、Morita Yusuke、Matsuda Shintaro、Watanabe Shin、Kuwabara Yasuhide、Ono Koh、Imai Masao、Inoue Katsumi、Murai Tatsuya、Inada Tsukasa、Tanaka Masaru、Kita Toru、Kimura Takeshi、Nishi Eiichiro
  • Journal Title: Int J Cardiol. Volume: 243 Pages: 1-8
  • DOI: 10.1016/j.ijcard.2017.04.047
  • NAID: 130007900462
  • Peer Reviewed
• [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity (2019)
  • Author(s): Ohno M, Matsuura H., Makiyama T., Nishi K., Iwasaki H., Matsuda S., Kita T., Kimura T., and Nishi E.
  • Organizer: ESC congress
  • Int'l Joint Research
• [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity (2019)
  • Author(s): Ohno M, Matsuura H., Makiyama T., Nishi K., Iwasaki H., Matsuda S., Kita T., Kimura T., and Nishi E.
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity (2019)
  • Author(s): Mikiko Ohno, Hiroshi Matsuura, Takeru Makiyama, Hirotaka Iwasaki, Shintaro Matsuda, Eiichiro Nishi
  • Organizer: 第83回日本循環器学会総会
• [Presentation] Nardilysin regulates cardiac dynamics and cardiac sympathetic innervation through modulating p75NTR shedding (2018)
  • Author(s): 大野美紀子, 西 清人, 平岡 義範, 新妻 晋一郎, 西城 さやか, 坂本 二郎, 陳 博俊, 森田 雄介, 松田 真太郎, 椋本 淑子, 清成 寛, 松浦 博, 北 徹, 木村 剛, 西 英一郎.
  • Organizer: 神経科学大会
• [Presentation] Nardilysin is a Promising Biomarker for the Early Diagnosis of Acute Coronary Syndrome. (2018)
  • Author(s): Ohno M, Chen P-M, Hiwasa T, Nishi K, Saijo S, Sakamoto J, Morita Y, Watanabe S, Kuwabara Y, Ono K, Imai M, Inoue K, Murai T, Kita T, Kimura T, and Nishi E.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] 急性冠症候群における新規バイオマーカー「ナルディライジン」の有用性についての検討 (2017)
  • Author(s): 大野美紀子、陳博俊、日和佐隆樹、西清人、西城さやか、森田雄介、松田真太郎、木村剛、西英一郎.
  • Organizer: 第22回日本病態プロテアーゼ学会
• [Presentation] 多機能タンパク質NardilysinのACSバイオマーカーとしての意義 (2017)
  • Author(s): 大野美紀子
  • Organizer: 第3回Cardiac Biomarker研究会
  • Invited
• [Presentation] ナルディライジンは神経栄養因子受容体(p75NTR)のシェディングを介して心臓交感神経の分布を制御する (2017)
  • Author(s): 大野美紀子, 西 清人, 平岡 義範, 新妻 晋一郎, 西城 さやか, 坂本 二郎, 陳 博俊, 森田 雄介, 松田 真太郎, 椋本 淑子, 清成 寛, 松浦 博, 北 徹, 木村 剛, 西 英一郎
  • Organizer: 生命科学系学会合同年次大会(第40回日本分子生物学会年会)
• [Remarks] 滋賀医科大学薬理学講座ホームページ
  • URL: http://www.shiga-med.ac.jp/pharm/
• [Remarks] 滋賀医科大学薬理学講座
  • URL: http://www.shiga-med.ac.jp/pharm/