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

Sameer Ather, Wei Wang, Qiongling Wang, Na Li, Mark E. Anderson, Xander H.T. Wehrens

Research output: Contribution to journalArticlepeer-review

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) Ca2+ 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 Ca2+ leak and VT are poorly understood. Objective: To test whether enhanced Ca 2+/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.

Original languageEnglish (US)
Pages (from-to)592-599
Number of pages8
JournalHeart Rhythm
Volume10
Issue number4
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

Keywords

  • Ca/ calmodulin-dependent protein kinase II
  • Cardiac arrhythmias
  • Duchenne muscular dystrophy
  • Mouse model
  • Ryanodine receptor
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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