title: Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy.
abstract: BACKGROUND
  Patients with Duchenne muscular dystrophy (DMD) are at risk of developing cardiomyopathy and cardiac arrhythmias. Studies in a mouse model of DMD revealed that enhanced sarcoplasmic reticulum (SR) Ca(2+) leak contributes to the pathogenesis of cardiac dysfunction. In view of recent data suggesting the involvement of altered phosphorylation and oxidation of the cardiac ryanodine receptor (RyR2)/Ca(2+) release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca(2+) leak by reducing RyR2 oxidation.
  
  
  RESULTS
  Confocal Ca(2+) imaging and single RyR2 channel recordings revealed that both inhibition of S2808 or S2814 phosphorylation, and inhibition of oxidation could normalize RyR2 activity in mdx mice. Moreover, Western blotting revealed that genetic inhibition of RyR2 phosphorylation at S2808 or S2814 reduced RyR2 oxidation. Production of reactive oxygen species (ROS) in myocytes from mdx mice was reduced by both inhibition of RyR2 phosphorylation or the ROS scavenger 2-mercaptopropionyl glycine (MPG). Finally, it was shown that ROS production in mdx mice is proportional to the activity of RyR2-mediated SR Ca(2+) leak, and likely generated by Nox2.
  
  
  CONCLUSIONS
  Increased ROS production in the hearts of mdx mice drives the progression of cardiac dysfunction. Inhibition of RyR2 phosphorylation can suppress SR Ca(2+) leak in mdx mouse hearts in part by reducing RyR2 oxidation.
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Medicine/Cardiology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wehrens@bcm.edu.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D006321:Heart / Q000503:physiopathology*; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Duchenne muscular dystrophy; Oxidation; Phosphorylation; Reactive oxygen species; Ryanodine receptor type 2