title: Inhibition of CaMKII phosphorylation of RyR2 prevents inducible ventricular arrhythmias in mice with Duchenne muscular dystrophy.
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.
authors.affiliation: Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Ather
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005786:Gene Expression Regulation; D051379:Mice; D018101:Mice, Inbred mdx; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012680:Sensitivity and Specificity; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2