Investigation of key molecules for exercise-induced bradycardia: involvement of oxidative stress in functional regulation of the cardiac pacemaker

• Project/Area Number: 18K15017
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Ritsumeikan University
• Principal Investigator: NAKAO Shu 立命館大学, 生命科学部, 助教 (30646956)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 心臓 / 不整脈 / 心臓刺激伝導系 / 分子生物学 / 生理学 / 酸化ストレス / 運動 / 代謝 / 刺激伝導系 / 細胞内シグナル伝達系

Outline of Final Research Achievements

We have investigated the underlying mechanisms of exercise-induced bradyarrhythmias using exercise mouse model, but signaling molecules involved in these arrhythmias remain unknown. In this study, we hypothesized whether exercise-induced oxidative stress causes pacemaker dysfunction. Transcriptome analysis from sedentary and trained mouse sinoatrial node, primary pacemaking site, revealed over 4,000 genes were downregulated by exercise, and cardiac pacemaking genes were also affected, whereas the expression pattern of genes related to oxidative stress were not significantly changed. Moreover, anti-oxidant agent resveratrol treatment slightly improved exercise-induced slowed heart rate.

Academic Significance and Societal Importance of the Research Achievements

有酸素運動によって過剰に増加する酸化ストレスが運動誘発性不整脈に関与していることを示唆する傍証は得られていないが、遺伝子発現の網羅的解析によって予想外の遺伝子群の変動が認められた。今後、従来より関連付けられている「運動と酸化ストレス」だけでなく、本研究から得られた新たな視点からメカニズム解明を目指すことで、不整脈全般に関わる新規病態因子の発見につながっていくことを期待する。

Research Products

• [Int'l Joint Research] University of Manchester(英国)
• [Int'l Joint Research] University of Liverpool(英国)
• [Int'l Joint Research] University of Montpellier(フランス)
• [Int'l Joint Research] University of Manchester(英国)
• [Int'l Joint Research] University of Copenhagen(デンマーク)
• [Int'l Joint Research] Universite de Montpellier(フランス)
• [Int'l Joint Research] University of Manchester(英国)
• [Int'l Joint Research] Universite de Montpellier(フランス)
• [Journal Article] Pathological Features of the Atrioventricular Conduction System in Feline Cases of Third-degree Atrioventricular Block (2020)
  • Author(s): 佐々木崇文、中尾周、木村勇介、平川篤、町田登
  • Journal Title: Journal of the Japan Veterinary Medical Association Volume: 73 Issue: 6 Pages: 315-320
  • DOI: 10.12935/jvma.73.315
  • NAID: 130007878408
  • ISSN: 0446-6454, 2186-0211
  • Year and Date: 2020-06-20
  • Peer Reviewed / Open Access
• [Journal Article] Silencing miR-370-3p rescues funny current and sinus node function in heart failure. (2020)
  • Author(s): Yanni J, D'Souza A, Wang Y, Li N, Hansen BJ, Zakharkin SO, Smith M, Hayward C, Whitson BA, Mohler PJ, Janssen PML, Zeef L, Choudhury M, Zi M, Cai X, Logantha SJRJ, Nakao S, Atkinson A, Petkova M, Doris U, Ariyaratnam J, Cartwright EJ, Griffiths-Jones S, Hart G, Fedrov VV, Oceandy D, Dobrzynski H, Boyett MR
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 11279-11279
  • DOI: 10.1038/s41598-020-67790-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 洞房結節におけるインパルス生成の分子基盤と臨床． (2020)
  • Author(s): 中尾周、宮﨑聖也、水口幹公、柳澤和輝、川村晃久
  • Journal Title: 動物の循環器 Volume: 53 Pages: 53-63
  • NAID: 130008076285
  • Peer Reviewed / Open Access
• [Journal Article] 運動誘発性不整脈のメカニズム． (2020)
  • Author(s): 中尾 周、川村晃久
  • Journal Title: Bio Clinica Volume: 35 Pages: 753-757
• [Journal Article] Applications of induced pluripotent stem cells in disease modelling and drug development for heart diseases. (2020)
  • Author(s): Nakao S, Ihara D, Hasegawa K, Kawamura T
  • Journal Title: Eur Cardiol Rev Volume: 15
  • DOI: 10.15420/ecr.2019.03
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chimeric G-CSF receptor-mediated STAT3 activation contributes to efficient induction of cardiomyocytes from mouse induced pluripotent stem cells. (2019)
  • Author(s): Tsukamoto T, Sogo T, Ueyama T, Nakao S, Harada Y, Ihara D, Akagi Y, Kida YS, Hasegawa K, Nagamune T, Kawahara M, Kawamura T.
  • Journal Title: Biotechnol J Volume: - Issue: 2 Pages: 1900052-1900052
  • DOI: 10.1002/biot.201900052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emerging roles of neuronal Ca2+ sensor-1 in cardiac and neuronal tissues: a mini review (2019)
  • Author(s): Nakamura TY., Nakao S, Wakabayashi S
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 12 Pages: 56-56
  • DOI: 10.3389/fnmol.2019.00056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cardiac adaptation to exercise: adverse effects of excessive physical training and its molecular basis. Session3. Regeneration, development and remodeling of the heart. (2021)
  • Author(s): Nakao S
  • Organizer: ISCMF 2021 Virtual Symposium
  • Int'l Joint Research / Invited
• [Presentation] Gene expression profiling of the sinoatrial node in mice: the effect of endurance exercise. (2020)
  • Author(s): Miyazaki S, Mizuguchi M, Ishida T, Ueyama T, Sogo T, Nakao S, Kawamura T
  • Organizer: 第97回日本生理学会大会
• [Presentation] Transcriptome analysis of the sinoatrial node in mice with exercise-induced bradycardia. (2020)
  • Author(s): Miyazaki S, Mizuguchi M, Ishida T, Hasegawa K, Nakao S, Kawamura T
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] シンポジウム「心臓刺激伝導系の基礎と病的変化」：心臓ポンプ運動を司る心臓刺激伝導系の役割：インパルス生成・伝播の分子基盤 (2020)
  • Author(s): 中尾 周
  • Organizer: 第111回日本獣医循環器学会
  • Invited
• [Presentation] P3826 Gene therapy for cardiac conduction system dysfunction in heart failure. (2019)
  • Author(s): Stuart L, Oh IY, Wang Y, Nakao S, Starborg T, Yanni-Gerges J, Kitmitto A, Dobrzynski H, Cartwright EJ, Oceandy D, Boyett MR
  • Organizer: ESC Congress 2019 (World Congress of Cardiology)
  • Int'l Joint Research
• [Presentation] 心臓刺激伝導系および右心房筋における持久運動による遺伝子発現パターンの変化 (2019)
  • Author(s): 宮崎聖也、呉自飛、水口幹公、吉澤琢雄、徳永千尋、井原大、原田恭弘、長谷川浩二、植山萌恵、十河孝浩、中尾周、川村晃久
  • Organizer: 第4回J-ISCP年次学術集会
• [Presentation] 抗がん剤ドキソルビシンの心毒性：マウス心臓刺激伝導系への影響 (2019)
  • Author(s): 水口幹公、宮﨑聖也、吉澤琢雄、呉 自飛、赤間友美、井原 大、植山萌恵、十河孝浩、中尾 周、川村晃久
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Disease-specific induced-pluripotent stem cells in pathophysiological analysis and drug development for heart diseases (2019)
  • Author(s): Harada Y, Nakao S, Ihara D, Ueyama T, Hasegawa K, Kawamura T
  • Organizer: 16th CVCT Forum
  • Int'l Joint Research
• [Presentation] Analysis of exercise-induced bradyarrhythmias: from pathogenesis to regeneration of cardiac pacemaker cells. (2019)
  • Author(s): Nakao S
  • Organizer: Cutting-Edge Biological Science and Technology Encounter 2019
  • Int'l Joint Research / Invited
• [Presentation] Pacemaking ion channel remodelling underlies chronic exercise-induced atrioventricular block (2019)
  • Author(s): Nakao S, D’Souza A, Mesirca P, Trussell T, Zi M, Logantha SJRJ, Cartwright E, Mangoni ME, Dobrzynski H, Boyett MR
  • Organizer: 9th FAOPS Congress
  • Int'l Joint Research
• [Presentation] Regulation of mitochondrial respiration, energy metabolism, and obesity by neuronal Ca2+-sensor-1 (2019)
  • Author(s): Nakamura-Nishitani TY, Nakao S, Wakabayashi S
  • Organizer: 9th FAOPS Congress
  • Int'l Joint Research
• [Presentation] 3D ultrastructure of the "arrhythmogenic" Purkinje fiber-ventricular junction in rabbit hearts (2018)
  • Author(s): Nakao S, Oh I-Y, Stuart L, Sitpura H, Yanni J, Logantha SJSR, Cai X, Dobrzynski H, Starborg T, Kitmitto A, Boyett MR
  • Organizer: 23rd International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] Role of aerobic metabolism in direct reprogramming to neurons (2018)
  • Author(s): Akagi Y, Harada Y, Ueyama T, Ihara D, Torii S, Nakagawa S, Sogo T, Nakao S, Kawamura T
  • Organizer: 23rd International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] The role of p53 localized in cytodol and mitochondria during reprogramming to iPS cells (2018)
  • Author(s): Akama T, Tenghattakorn A, Yamasaki M, Harada Y, Ihara D, Ueyama T, Sogo T, Nakao S, Kawamura T
  • Organizer: 23rd International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] Transcription-independent functions of local p53: a possible target to improve cardiac cell therapy (2018)
  • Author(s): Tenghattakorn A, Akama T, Yamasaki M, Harada Y, Ihara D, Ueyama T, Sogo T, Nakao S, Kawamura T
  • Organizer: 23rd International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] miR17-92 cluster promotes efficiency of direct reprogramming to induced cardiomyocytes (2018)
  • Author(s): Ueyama T, Ihara D, Harada Y, Akagi Y, Arima D, Nakagawa S, Sogo T, Nakao S, Kawamura T
  • Organizer: 23rd International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] 硬骨魚類における心臓刺激伝導系の立体組織構造 (2018)
  • Author(s): 中尾 周，Jeziorska M，Boyett MR
  • Organizer: 第108回日本獣医循環器学会
• [Presentation] Why do athletes have heart block? (2018)
  • Author(s): D’Souza A, Trussell T, Nakao S, Mesirca P, Zi M, Logantha SJRJ, Li J, Wang Y, Jespersen T, Bulh R, Cartwright EJ, Mangoni ME, Boyett MR, Dobrzynski H
  • Organizer: Europhysiology 2019
  • Int'l Joint Research
• [Presentation] iPS細胞へのリプログラミングにおける細胞質およびミトコンドリアに局在するp53の解析 (2018)
  • Author(s): 赤間 友美、山崎 基春、植山 萌恵、井原 大、原田 恭弘、鳥居 昇平、中川 沙恵、赤木 祐香、十河 孝浩、中尾 周、川村 晃久
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] ダイレクトリプログラミング過程における好気性代謝と細胞老化の役割 (2018)
  • Author(s): 赤木 祐香、原田 恭弘、植山 萌恵、井原 大、中川 沙恵、山崎 基春、有馬 大貴、石田 智明、徳永 千尋、十河 孝浩、中尾 周、川村 晃久
  • Organizer: 第41回日本分子生物学会年会
• [Remarks] 立命館大学 研究者学術情報データベース
  • URL: https://research-db.ritsumei.ac.jp/rithp/k03/resid/S001494
• [Remarks] ORCID (Connecting Research and Researchers)
  • URL: https://orcid.org/0000-0001-8990-1179
• [Remarks] 立命館大学 研究者学術情報データベース
  • URL: http://research-db.ritsumei.ac.jp/Profiles/134/0013394/profile.html
• [Remarks] ORCiD
  • URL: https://orcid.org/0000-0001-8990-1179
• [Remarks] KAKEN 科学研究費助成事業データベース
  • URL: https://nrid.nii.ac.jp/ja/nrid/1000030646956/