Elucidation of the pathogenesis of cardiovascular diseases by stress memory through interorgan cooperation

• Project/Area Number: 17H04171
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Fujiu Katsuhito 東京大学, 医学部附属病院, 特任准教授 (30422306)
• Co-Investigator(Kenkyū-buntansha): 眞鍋 一郎 千葉大学, 大学院医学研究院, 教授 (70359628)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 心不全 / 心臓マクロファージ / 臓器間連携 / マクロファージ / 心臓 / 不整脈 / 突然死 / 免疫細胞 / 炎症 / 臓器連関

Outline of Final Research Achievements

In this study, it was clarified that there is a system to correct homeostasis of the heart when a pressure load is newly applied to the heart by cooperation of the heart, brain and kidney. When mice were created in which this homeostatic mechanism does not function, they developed heart failure and died. Therefore, this new homeostatic mechanism is likely to be associated with the development of heart failure.
Furthermore, as a new cooperation between organs, we discovered the cooperation of the heart, brain, and organ X. In this organ X, a response to the stress on the heart is being performed, and this reaction changed the response to the stress of the heart. This suggested that organ X was also involved in the development of heart failure.

Academic Significance and Societal Importance of the Research Achievements

心臓の中には実際に心臓を動かす心筋細胞以外に複数の細胞が存在しています。その中で心臓の全細胞の約１％程度しか存在しない、心臓マクロファージというマイナーな細胞に注目して研究を行いました。その結果、この心臓マクロファージが心臓全体の機能をコントロールしていることを発見しました。マクロファージからはアンフィレギュリンというたんぱく質が分泌されます。このたんぱく質は心筋細胞に働き心筋細胞の働きを強くし、心臓への負担に耐えられるようにしていることを見つけました。このたんぱく質を働かせなくしたマウスも心臓に少しでも負担がかかると心臓病になってしまいます。このたんぱく質は治療に応用できる可能性があります。

Research Products

• [Journal Article] Response to Comment on “Ghost cytometry” (2019)
  • Author(s): Sadao Ota, Ryoichi Horisaki, Yoko Kawamura, Masashi Ugawa, Issei Sato, Hiroaki Adachi, Satoko Yamaguchi, Katsuhito Fujiu, Kayo Waki, Hiroyuki Noji
  • Journal Title: Science Volume: 364 Issue: 6437
  • DOI: 10.1126/science.aav3136
  • Peer Reviewed
• [Journal Article] Can Anti-inflammatory Therapy Prevent Atrial Fibrillation in Myocardial Infarction Patients? (2018)
  • Author(s): Nakayama Y, Fujiu K
  • Journal Title: International Heart Journal Volume: 59 Issue: 1 Pages: 3-5
  • DOI: 10.1536/ihj.17-662
  • NAID: 130006321432
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation and cellular communication (2017)
  • Author(s): Fujiu K, Shibata M, Nakayama Y, Ogata F, Matsumoto S, Noshita K, Iwami S, Nakae S, Komuro I, Nagai R, Manabe I
  • Journal Title: Nature Medicine Volume: 印刷中 Issue: 5 Pages: 611-622
  • DOI: 10.1038/nm.4326
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Testing the Feasibility and Usability of a Novel Smartphone-Based Self-Management Support System for Dialysis Patients: A Pilot Study (2017)
  • Author(s): Hayashi Aki、Yamaguchi Satoko、Waki Kayo、Fujiu Katsuhito、Hanafusa Norio、Nishi Takahiro、Tomita Hyoe、Kobayashi Haruka、Fujita Hideo、Kadowaki Takashi、Nangaku Masaomi、Ohe Kazuhiko
  • Journal Title: JMIR Research Protocols Volume: 6 Issue: 4 Pages: e63-e63
  • DOI: 10.2196/resprot.7105
  • Peer Reviewed
• [Journal Article] Cardiac Resynchronization Therapy in Patients with Ebstein's Anomaly (2017)
  • Author(s): Numata G, Amiya E, Kojima T, Fujiu K, Hatano M, Watanabe M, Komuro I
  • Journal Title: International Heart Journal Volume: 58 Issue: 5 Pages: 816-819
  • DOI: 10.1536/ihj.16-580
  • NAID: 130006179198
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Presentation] Renal Collecting Duct Epithelial Cell Controls Kidney Disease and Adaptation to Cardiac Stress through Tissue Macrophage Activation (2018)
  • Author(s): Katsuhito Fujiu
  • Organizer: ISN Frontiers Meetings
  • Int'l Joint Research / Invited
• [Presentation] Cardiac Macrophage is Required to Avoid Heart Failure and Cardiac Sudden Death after Pressure Overload (2017)
  • Author(s): Katsuhito Fujiu
  • Organizer: Keystone Symposia Conference: Mitochondria, Metabolism and Heart
  • Int'l Joint Research / Invited
• [Presentation] Cardiac Macrophage is a Novel Target of Regenerative Medicine on Arrhythmia, Regenerative Medicine and Arrhythmias (2017)
  • Author(s): Katsuhito Fujiu
  • Organizer: The joint meeting of the 10th Asia Pacific Heart Rhythm Society Scientific Session (APHRS 2017) and the 64th Annual Meeting of the Japanese Heart Rhythm Society (JHRS2017)
  • Int'l Joint Research / Invited
• [Presentation] HIS bundle pacing for bradycardia patients (2017)
  • Author(s): Katsuhito Fujiu
  • Organizer: The joint meeting of the 10th Asia Pacific Heart Rhythm Society Scientific Session (APHRS 2017) and the 64th Annual Meeting of the Japanese Heart Rhythm Society (JHRS2017)
  • Int'l Joint Research / Invited