Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice
Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice
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DOI：
10.1253/circj.cj-18-0743
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发表时间：
2019-02-01
影响因子：
3.3
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
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作者：
Prajapati, Rajesh;Fujita, Takayuki;Ishikawa, Yoshihiro
背景：有人认为，β-肾上腺素能受体（β-AR）下游信号分子之一 cAMP 直接激活的蛋白质（Epac）可能是治疗心律失常的有效靶点。然而，目前还没有关于Epac1抑制剂在体内的抗心律失常作用或心脏副作用的报道。方法和结果：在本研究中，研究了Epac1在房性和室性心律失常发展中的作用。此外，我们还研究了 Epac1 选择性抑制剂 CE3F4 在治疗小鼠心律失常中的有效性。在 Epac1 敲除 (Epac1-KO) 小鼠中，心房颤动 (AF) 的持续时间比野生型小鼠短。在 calsequestrin2 基因敲除小鼠中，Epac1 缺陷导致室性心律失常减少。在心房和心室肌细胞中，Epac1-KO 小鼠中肌浆网 (SR) Ca2+ 渗漏（心律失常的主要触发因素）和自发 SR Ca2+ 释放 (SCR) 均减弱。一致的是，CE3F4 治疗显着预防了小鼠的房颤和室性心律失常。此外，CE3F4 治疗心房肌细胞和心室肌细胞的 SR Ca2+ 渗漏和 SCR 均受到显着抑制。重要的是，足以发挥抗心律失常作用的CE3F4剂量并未显着影响心脏功能。结论：这些发现表明Epac1参与房性和室性心律失常的发展。 CE3F4 是一种 Epac1 选择性抑制剂，可预防小鼠的房性和室性心律失常。
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.