Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

被引:18
|
作者
Prajapati, Rajesh [1 ]
Fujita, Takayuki [1 ]
Suita, Kenji [1 ,2 ]
Nakamura, Takashi [1 ]
Cai, Wenqian [1 ]
Hidaka, Yuko [1 ]
Umemura, Masanari [1 ]
Yokoyama, Utako [1 ]
Knollmann, Bjorn C. [3 ]
Okumura, Satoshi [2 ]
Ishikawa, Yoshihiro [1 ]
机构
[1] Yokohama City Univ, Grad Sch Med, Cardiovasc Res Inst, Yokohama, Kanagawa, Japan
[2] Tsurumi Univ, Sch Dent Med, Yokohama, Kanagawa, Japan
[3] Vanderbilt Univ, Sch Med, Vanderbilt Ctr Arrhythmia Res & Therapeut, Nashville, TN 37212 USA
基金
日本学术振兴会;
关键词
Arrhythmia; Atrial fibrillation; Epac; Sympathetic nervous system; RETICULUM CA2+ LEAK; RYANODINE RECEPTOR PHOSPHORYLATION; CHRONIC HEART-FAILURE; EUROPEAN-SOCIETY; EPAC ACTIVATION; TASK-FORCE; FIBRILLATION; ASSOCIATION; INHIBITION; DISRUPTION;
D O I
10.1253/circj.CJ-18-0743
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of beta-adrenergic receptor (beta-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Conclusions: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.
引用
收藏
页码:295 / +
页数:21
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