期刊
HEART RHYTHM
卷 10, 期 4, 页码 592-599出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2012.12.016
关键词
Cardiac arrhythmias; Ca2+/ calmodulin-dependent protein kinase II; Mouse model; Ryanodine receptor; Duchenne muscular dystrophy; Ventricular tachycardia
资金
- American Heart Association (AHA) SCA predoctoral fellowship
- Alkek Foundation from Baylor College of Medicine
- AHA SCA postdoctoral fellowship
- AHA
- National Institutes of Health (NIB) [HL089598, HL091947]
- Muscular Dystrophy Association [69238]
- NIH [HL079031, HL096652, HL113001, HL070250]
- Fondation Leducq Alliance for CaMKII signaling
BACKGROUND Ventricular tachycardia (VT) is the second most common cause of death in patients with Duchenne muscular dystrophy (DMD). Recent studies have implicated enhanced sarcoplasmic reticulum (SR) Ca2+ leak via type 2 ryanodine receptor (RyR2) as a cause of VT in the mdx mouse mode l of DMD. However, the signaling mechanisms underlying induction of SR Ca2+ leak and VT are poorly understood. OBJECTIVE To test whether enhanced Ca2+ /calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2 underlies SR Ca2+ leak and induction of VT in mdx mice. METHODS Programmed electrical stimulation was performed on anesthetized mice and confocal imaging of Ca2+ release events in isolated ventricular myocytes. RESULTS Programmed electrical stimulation revealed inducible VT in mdx mice, which was inhibited by CaMKII inhibition or mutation S2814A in RyR2. Myocytes from mdx mice exhibited more Ca2+ sparks and Ca2+ waves compared with wild-type mice, in particular at faster pacing rates. Arrhythmogenic Ca2+ waves were inhibited by CaMKII but not by protein kinase A inhibition. Moreover, mutation S2814A but not S2808A in RyR2 suppressed spontaneous Ca2+ waves in myocytes from mdx mice. CONCLUSIONS CaMKII blockade and genetic inhibition of RyR2-S2814 phosphorylation prevent VT induction in a mouse model of DMD. In ventricular myocytes from mdx mice, spontaneous Ca2+ sparks and Ca2+ waves can be suppressed by CaMKII inhibition or mutation S2814A in RyR2. Thus, the inhibition of CaMKII-induced SR Ca2+ leak might be a new strategy to prevent arrhythmias in patients with DMD without heart failure.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据