Analysis of potential molecular targets in the beta-adrenergic receptor signal pathway for new drug therapy of catecholamine-induced arrhythmias

• Project/Area Number: 24790219
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Yokohama City University
• Principal Investigator: SUITA KENJI 横浜市立大学, 医学(系)研究科(研究院), 特任助手 (90569542)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• 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 / ベータアドレナリン受容体シグナル伝達 / セカンドメッセンジャー / カテコラミン / サイクリックAMP / Epac1

Outline of Final Research Achievements

Adenylyl cyclase (AC) and Epac, a target molecule of cAMP, play critical roles in beta-adrenergic receptor (β-AR) signaling in heart. The usefulness of β-AR antagonist (β-blocker) for the treatment of catecholamine-induced AF and ventricular arrhythmias is established. However, even low dosage of β-blockers exert negative-inotropic effect and may cause a deterioration of heart function. We found that vidarabine, an anti-herpesvirus agent, is a selective inhibitor of cardiac AC subtype. Here, we evaluated the anti-arrhythmic effect of vidarabine using our AF model, in which the duration of AF is strikingly elongated by noradrenaline, and a previously established model of ventricular arrhythmias.
Results indicate that vidarabine prevents catecholamine-induced AF and ventricular arrhythmias without deterioration of heart function. On the other hand, the AF duration of Epac1 gene-knockout mice was shorter than that of wild-type mice, suggesting that Epac1 plays an important role in AF.

Research Products

• [Journal Article] Oscillation of cAMP and Ca(2+) in cardiac myocytes: a systems biology approach (2015)
  • Author(s): Kamide T, Okumura S, Ghosh S, Shinoda Y, Mototani Y, Ohnuki Y, Jin H, Cai W, Suita K, Sato I, Umemura M, Fujita T, Yokoyama U, Sato M, Furutani K, Kitano H, Ishikawa Y
  • Journal Title: The Journal of Physiological Sciences Volume: 65(2) Issue: 2 Pages: 195-200
  • DOI: 10.1007/s12576-014-0354-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Coupling of beta1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes. (2015)
  • Author(s): Tsunematsu T, Okumura S, Mototani Y, Ohnuki Y, Jin H, Cai W, SuitaK, Sato I, Umemura M, Yokoyama U, Sato M, Fujita T, and Ishikawa Y.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 458 Issue: 3 Pages: 531-535
  • DOI: 10.1016/j.bbrc.2015.01.149
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of Epac1 decreases phosphorylation of phospholamban and protects the heart against stresses (2014)
  • Author(s): Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y
  • Journal Title: Journal of Clinical Investigation Volume: 印刷中
  • Peer Reviewed
• [Presentation] 抗ヘルペス薬による心房細動抑制． (2014)
  • Author(s): 吹田憲治、藤田孝之、奥村敏、石川義弘
  • Organizer: 第131回日本薬理学会関東部会
  • Place of Presentation: 横浜市立大学福浦キャンパス看護棟（横浜）
  • Year and Date: 2014-10-11
• [Presentation] Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced atrial fibrillation in mice. (2014)
  • Author(s): Suita K, Fujita T, Cai W, Hidaka Y, Jin H, Jin M, Okumura S, Ishikawa Y
  • Organizer: European Society of Cardiology, Annual Congress 2014
  • Place of Presentation: バルセロナ（スペイン）
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] 心臓型アデニル酸シクラーゼの選択的阻害剤ビダラビンによる心房細動抑制． (2014)
  • Author(s): 吹田憲治、藤田孝之、蔡文倩、金、奥村敏、石川義弘
  • Organizer: 第35回日本循環制御医学会総会
  • Place of Presentation: 九州大学医学部百年講堂（福岡）
  • Year and Date: 2014-07-04 – 2014-07-05
• [Presentation] Vidarabine, an anti-herpesvirus agent, attenuates Ca2+ leak from sarcoplasmic reticulum in cardiomyocytes and prevents atrial fibrillation in mice (2014)
  • Author(s): Suita K, Cai W, Jin H, Jin M, Fujita T, Okumura S, Ishikawa Y
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都）
• [Presentation] 心臓型アデニル酸シクラーゼの選択的阻害剤はCalsequestrin 2ノックアウトマウスに誘発した心室性不整脈を抑制する (2014)
  • Author(s): 吹田憲治、藤田孝之、金慧玲、蔡文倩、奥村敏、石川義弘
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学郡元キャンパス（鹿児島県）
• [Presentation] 心臓型アデニル酸シクラーゼの選択的阻害剤ビダラビンによる不整脈治療の可能性 (2013)
  • Author(s): 吹田憲治、藤田孝之、石川義弘
  • Organizer: 生理学研究所研究会2013
  • Place of Presentation: 生理学研究所（愛知県）
• [Presentation] Inhibitor of cardiac adenylyl cyclase prevents atrial fibrillation in mice (2013)
  • Author(s): Suita K, Cai W, Jin H, Jin M, Fujita T, Okumura S, Ishikawa Y
  • Organizer: HD Physiology, the 2nd International Symposium 2013
  • Place of Presentation: MARUNOUCHI MY PLAZA Hall（東京都）
• [Presentation] 抗ヘルペス剤ビダラビンはマウスの心房細動を抑制する (2013)
  • Author(s): 吹田憲治
  • Organizer: 第９０回日本生理学会大会
  • Place of Presentation: タワーホール船堀（東京都）
• [Remarks] 横浜市立大学循環制御医学研究室ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/index.html