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Heart Rhythm. 2013 Apr;10(4):592-9. doi: 10.1016/j.hrthm.2012.12.016. Epub 2012 Dec 12.

Inhibition of CaMKII phosphorylation of RyR2 prevents inducible ventricular arrhythmias in mice with Duchenne muscular dystrophy.

Author information

1
Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

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) Ca(2+) leak via type 2 ryanodine receptor (RyR2) as a cause of VT in the mdx mouse model of DMD. However, the signaling mechanisms underlying induction of SR Ca(2+) leak and VT are poorly understood.

OBJECTIVE:

To test whether enhanced Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2 underlies SR Ca(2+) leak and induction of VT in mdx mice.

METHODS:

Programmed electrical stimulation was performed on anesthetized mice and confocal imaging of Ca(2+) 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 Ca(2+) sparks and Ca(2+) waves compared with wild-type mice, in particular at faster pacing rates. Arrhythmogenic Ca(2+) waves were inhibited by CaMKII but not by protein kinase A inhibition. Moreover, mutation S2814A but not S2808A in RyR2 suppressed spontaneous Ca(2+) 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 Ca(2+) sparks and Ca(2+) waves can be suppressed by CaMKII inhibition or mutation S2814A in RyR2. Thus, the inhibition of CaMKII-induced SR Ca(2+) leak might be a new strategy to prevent arrhythmias in patients with DMD without heart failure.

PMID:
23246599
PMCID:
PMC3605194
DOI:
10.1016/j.hrthm.2012.12.016
[Indexed for MEDLINE]
Free PMC Article

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