Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy. (December 2015)

• Record Type: Journal Article
• Authors: Wang, Qiongling; Wang, Wei; Wang, Guoliang; Rodney, George G.; Wehrens, Xander H.T.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 89:Part B(2015)
• Page Start: 177
• Page End: 184
• Publication Date: 2015-12
• Subjects: CaMKII calcium/calmodulin-dependent protein kinase II -- CaSpF calcium sparks frequency -- DCFH-DA 5-(6)-chloromethyl-2, 7-dichlorodihydrofluorescein diacetate -- DHE dihydroethidium -- DMD Duchenne muscular dystrophy -- MPG N-2-mercaptopropionyl glycine -- NOS nitric oxide synthase -- NOX NADPH oxidase -- PKA protein kinase A -- PTM post-translational modification -- RNS reactive nitrogen species -- ROS reactive oxygen species -- RyR2 ryanodine receptor type 2 -- SR sarcoplasmic reticulum -- SERCA2a sarco/endoplasmic reticulum Ca2 +-ATPase; Duchenne muscular dystrophy -- Oxidation -- Phosphorylation -- Reactive oxygen species -- Ryanodine receptor type 2; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.11.009
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Methods and 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. Highlights: Increased ROS production contributes to cardiac dysfunction in mdx mice. Inhibition of RyR2 phosphorylation suppresses SR calcium leak in mdx mouse hearts. ROS production in mdx mice is proportional to RyR2-mediated SR calcium leak.