Development of new antiarrhythmic drugs alternative to beta blocker therapy

• Project/Area Number: 15K18973
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Tsurumi University (2016-2018); Yokohama City University (2015)
• Principal Investigator: Suita Kenji 鶴見大学, 歯学部, 学部助手 (90569542)
• Research Collaborator: ISHIKAWA Yoshihiro ; OKUMURA Satoshi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 不整脈 / 分子標的薬 / ベータアドレナリン受容体 / アデニル酸シクラーゼ / cAMP / Epac / βアドレナリン受容体 / 治療薬 / ベータアドレナリン受容体シグナル / 抗ヘルペス剤

Outline of Final Research Achievements

Excessive and chronic activation of sympathetic beta-adrenergic receptor (β-AR) signal are known to be a trigger of arrhythmias. In this study, we focus on the cardiac subtype of adenylate cyclase (AC) and exchanged protein directly activated by cAMP (Epac), a cAMP target protein, that mediates the β-AR signaling. We used the gene knockout mice to determine the role of both factors in arrhythmogenesis. Further, antiarrhythmic effect and adverse effects on cardiac function of inhibitors selective for cardiac AC and Epac1 subtypes were compared with a β-blocker. As a result, arrhythmia onset was significantly suppressed in AC5 and Epac1 knockout mice as compared to control mice. In addition, it has been clarified that inhibitors of both molecules prevented arrhythmias without deteriorating heart function as observed in β-blocker-treated mice.

Academic Significance and Societal Importance of the Research Achievements

β遮断薬は交感神経の過剰亢進による不整脈の治療に使用されてきたが、心機能を低下させる副作用は特に高齢者にとって問題である。超高齢社会をむかえたわが国において、副作用が少なく高齢者に安心して処方できる不整脈治療法の開発は重要な課題である。本研究の結果から、β受容体シグナル伝達経路を仲介する細胞内因子である心臓型AC5やEpac1をターゲットとした治療薬が、上記の要求を満たす有望な候補であることが明らかとなった。

Research Products

• [Journal Article] Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice (2019)
  • Author(s): Prajapati R, Fujita T, Suita K, Nakamura T, Cai W, Hidaka Y, Umemura M, Yokoyama U, Knollmann BC, Okumura S, Ishikawa Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 295-303
  • DOI: 10.1253/circj.CJ-18-0743
  • NAID: 130007557004
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced arrhythmias without adverse effect on heart function in mice (2018)
  • Author(s): Suita Kenji、Fujita Takayuki、Cai Wenqian、Hidaka Yuko、Jin Huiling、Prajapati Rajesh、Umemura Masanari、Yokoyama Utako、Sato Motohiko、Knollmann Bj?rn C.、Okumura Satoshi、Ishikawa Yoshihiro
  • Journal Title: Pfl?gers Archiv - European Journal of Physiology Volume: 未定 Issue: 6 Pages: 923-935
  • DOI: 10.1007/s00424-018-2121-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A New Drug Therapy for Heart Failure by Anti-Herpesvirus Agent, an Inhibitor of Cardiac Adenylyl Cyclase (2017)
  • Author(s): 吹田 憲治
  • Journal Title: CIRCULATION CONTROL Volume: 38 Issue: 2 Pages: 126-132
  • DOI: 10.11312/ccm.38.126
  • NAID: 130006067759
  • ISSN: 0389-1844
• [Journal Article] Cardiac overexpression of Epac1 in transgenic mice rescues lipopolysaccharide-induced cardiac dysfunction and inhibits Jak-STAT pathway. (2017)
  • Author(s): Huiling Jin, Takayuki Fujita, Meihua Jin, Reiko Kurotani, Iyuki Namekata, Shogo Hamaguchi, Yuko Hidaka, Wenqian Cai, Kenji Suita, Yoshiki Ohnuki, Yasumasa Mototani, Kouichi Shiozawa, Rajesh Prajapati, Chen Liang, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Hikaru Tanaka, Satoshi Okumura, Yoshihiro Ishikawa.
  • Journal Title: J Mol Cell Cardiol. Volume: 108 Pages: 170-180
  • DOI: 10.1016/j.yjmcc.2017.05.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vidarabine, an Anti-Herpes Virus Agent, Protects Against the Development of Heart Failure With Relatively Mild Side-Effects on Cardiac Function in a Canine Model of Pacing-Induced Dilated Cardiomyopathy (2016)
  • Author(s): T. Nakamura, T. Fujita, M. Kishimura, K. Suita, Y. Hidaka, W. Cai, M. Umemura, U. Yokoyama, M. Uechi, and Y. Ishikawa
  • Journal Title: Circulation Journal Volume: 80 Issue: 12 Pages: 2496-2505
  • DOI: 10.1253/circj.CJ-16-0736
  • NAID: 130005284971
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Role of phosphodiesterase 4 expression in the epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol． (2016)
  • Author(s): Ohnuki Y，Umeki D，Mototani Y，Shiozawa K，Nariyama M，Ito A，Kawamura N，Yagisawa Y，Jin H，Cai W，Suita K，Saeki Y，Fujita T，Ishikawa Y，Okumura S.
  • Journal Title: Physiological reports. Volume: 4 Issue: 10 Pages: e12791-e12791
  • DOI: 10.14814/phy2.12791
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction． (2016)
  • Author(s): Cai W，Fujita T，Hidaka Y，Jin H，Suita K，Prajapati R，Liang C，Umemura M，Yokoyama U，Sato M，Okumura S，Ishikawa Y
  • Journal Title: Biochem Biophys Res Commun. Volume: 475 Issue: 1 Pages: 1-7
  • DOI: 10.1016/j.bbrc.2016.04.123
  • Peer Reviewed
• [Journal Article] Norepinephrine-induced adrenergic activation strikingly increased the atrial fibrillation duration through β1- and α1-adrenergic receptor-mediated signaling in mice. (2015)
  • Author(s): Suita K, Fujita T, Hasegawa N, Cai W, Jin H, Hidaka Y, Prajapati R, Umemura M, Yokoyama U, Sato M, Okumura S, Ishikawa Y.
  • Journal Title: PLoS One. Volume: 23;10(7) Issue: 7 Pages: e0133664-e0133664
  • DOI: 10.1371/journal.pone.0133664
  • Peer Reviewed / Open Access
• [Journal Article] Protective Effects of Clenbuterol against Dexamethasone-Induced Masseter Muscle Atrophy and Myosin Heavy Chain Transition (2015)
  • Author(s): Umeki D, Ohnuki Y, Mototani Y, Shiozawa K, Suita K, Fujita T, Nakamura Y, Saeki Y, Okumura S
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0128263-e0128263
  • DOI: 10.1371/journal.pone.0128263
  • Peer Reviewed / Open Access
• [Presentation] Usefulness of anti-arrhythmic drug therapy targeting cardiac adenylyl cyclase. (2019)
  • Author(s): Suita K, Fujita T, Okumura S, Ishikawa Y
  • Organizer: FAOPS 9th Congress
  • Int'l Joint Research
• [Presentation] 強制的開口負荷が心機能および心筋細胞内シグナル伝達に与える影響の解析． (2018)
  • Author(s): 吹田憲治，八木澤由佳，大貫芳樹，梅木大輔，石川美佐緒, 伊藤愛子，川村直矢，中村芳樹，奥村敏
  • Organizer: 第60回日本歯科基礎医学会学術大会
• [Presentation] 抗ヘルペス剤ビダラビンによる酸化ストレスの低減を介した不整脈抑制作用． (2018)
  • Author(s): 吹田憲治，奥村敏，石川義弘
  • Organizer: 第27回日本病態生理学会大会
• [Presentation] 心臓型アデニル酸シクラーゼを標的とした新しい不整脈薬物治療． (2018)
  • Author(s): 吹田憲治，奥村敏，石川義弘
  • Organizer: 第57回日本生体医工学会大会
  • Invited
• [Presentation] Effect of enforced bite-opening on heart in mice. (2018)
  • Author(s): Suita K, Ohnuki Y, Okumura S
  • Organizer: 第95回日本生理学会大会
• [Presentation] Inhibition of cardiac adenylyl cyclase suppresses catecholamine-induced arrhythmias without deteriorating heart function． (2017)
  • Author(s): Suita K, Fujita T, Okumura S, Ishikawa Y
  • Organizer: 第94回日本生理学会大会，日本病態生理学会連携シンポジウム「自律神経研究の新しい流れと病態生理学」
  • Place of Presentation: アクトシティ浜松（静岡）
  • Year and Date: 2017-03-28
• [Presentation] 開口負荷がマウスの心房に与える影響． (2017)
  • Author(s): 吹田憲治，八木澤由佳，大貫芳樹，梅木大輔，石川美佐緒, 伊藤愛子，川村直矢，中村芳樹，奥村敏
  • Organizer: 第59回歯科基礎医学会学術大会
• [Book] 第57回日本生体医工学会大会 学会関連印象記 (2018)
  • Author(s): 吹田憲治
  • Total Pages: 3
  • Publisher: 日本循環制御医学会
• [Remarks] 横浜市立大学 循環医学制御講座ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/
• [Remarks] 鶴見大学 生理学講座ホームページ
  • URL: https://tsurumi-univ-seiri.jimdo.com/
• [Remarks] 横浜市立大学 循環制御医学講座ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/
• [Remarks] 鶴見大学 生理学講座ホームページ
  • URL: http://tsurumi-univ-seiri.jimdo.com/