| First Author | Prajapati R | Year | 2019 |
| Journal | Circ J | Volume | 83 |
| Issue | 2 | Pages | 295-303 |
| PubMed ID | 30518738 | Mgi Jnum | J:295620 |
| Mgi Id | MGI:6454130 | Doi | 10.1253/circj.CJ-18-0743 |
| Citation | Prajapati R, et al. (2019) Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice. Circ J 83(2):295-303 |
| abstractText | 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) Ca(2+) leak, a major trigger of arrhythmias, and spontaneous SR Ca(2+) release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca(2+) 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. |
