The usefulness of exchanged protein directly activated by cAMP (Epac)1-inhibiting therapy for prevention of heart disease.

• Project/Area Number: 17K15560
• 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: CAI WENQIAN 横浜市立大学, 医学研究科, 客員研究員 (00751512)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Epac1 / 不整脈 / 心不全 / Epac / 循環器 / 生理学

Outline of Final Research Achievements

Treatment with β-blockers has been established as extremely important in suppressing the progression of heart failure and improving the prognosis. However, the side effect of β-blockers that exacerbates heart failure is often a major problem. We have shown that Epac1 selectively mediates harmful effects of catecholamines. In cardiomyocytes, CE3F4, an Epac1 selective inhibitor, suppressed Ca2+ leakage from the endoplasmic reticulum, which is an important mechanism of arrhythmia development. Furthermore, in both mouse arrhythmia models of pacing-induced atrial fibrillation and ventricular arrhythmia in calsequestrin 2 deficient mice, CE3F4 administration showed an inhibitory effect on arrhythmia. These results suggest that Epac inhibitors may be useful as therapeutic agents for arrhythmia.

Academic Significance and Societal Importance of the Research Achievements

不整脈治療を要する患者は，心機能が低下していることが多く，β遮断薬の心機能抑制の副作用は投与時にしばしば問題になる．結果として十分な不整脈治療が行えなくなる場合もあるし，何とか投与可能であっても，投与開始時に心不全発症などについて極めて細かい注意を払う必要がある．本研究で, Epac阻害剤が心機能抑制などの副作用が極めて少ない，心不全，不整脈治療薬として有用であることが示されることが期待できる．これは，これまで低心機能などで副作用の危険からβ遮断薬が内服できず，その有用性の享受を断念せざるを得なかった多くの患者のQOLや予後の改善につながるものである．臨床で極めて有用なものとなると考えられる．

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] Correction to: Epac activation inhibits IL-6-induced cardiac myocyte dysfunction. (2019)
  • Author(s): Jin H, Fujita T, Jin M, Kurotani R, Hidaka Y, Cai W, Suita K, Prajapati R, Liang C, Ohnuki Y, Mototani Y, Umemura M, Yokoyama U, Sato M, Okumura S, Ishikawa Y.
  • Journal Title: J Physiol Sci. Volume: - Issue: 3 Pages: 557-557
  • DOI: 10.1007/s12576-019-00661-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of Epac1 in the development of ventricular arrhythmia in mice. (2018)
  • Author(s): Rajesh Prajapati, Takayuki Fujita, Kenji Suita, Takashi Nakamura, Wenqian Cai, Yuko Hidaka, Satoshi Okumura, Yoshihiro Ishikawa
  • Organizer: 第28回日本病態生理学会大会
• [Presentation] 不整脈発症における Epac1 の役割 (2018)
  • Author(s): 藤田 孝之, プラジャパティ ラジェシュ, 中村 隆, 蔡 文倩, 日高 祐子, 吹田 憲 治, 奥村 敏, 石川 義弘
  • Organizer: 第9回アジア・オセアニア生理学会連合2019年大会
  • Int'l Joint Research
• [Presentation] 不整脈発症におけるEpac1の役割 (2017)
  • Author(s): 藤田孝之、ブラジャパティ ラジェシュ、中村隆、蔡文倩、日高祐子、吹田憲治、奥村敏、石川義弘
  • Organizer: 第95回日本生理学会大会
• [Presentation] Epac1 plays an important role in the development of atrial fibrillation in mice (2017)
  • Author(s): Rajesh Prajapati，Takayuki Fujita，Takashi Nakamura，Kenji Suita，Wenqian Cai，Yuko Hidaka，Yoshihiro Ishikawa
  • Organizer: 第27回日本病態生理学会大会