Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy.
Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy.
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DOI：
10.1016/j.yjmcc.2015.11.009
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发表时间：
2015-12
影响因子：
5
通讯作者：
Wehrens XH
中科院分区：
文献类型：
--
作者：
Wang Q;Wang W;Wang G;Rodney GG;Wehrens XH
杜氏肌营养不良症（DMD）患者有发生心肌病和心律失常的风险。在DMD小鼠模型中的研究显示，增强的肌浆网（SR）Ca 2+渗漏有助于心功能不全的发病机制。鉴于最近的数据表明，心脏ryanodine受体（RyR 2）/Ca 2+释放通道的磷酸化和氧化改变的参与，我们假设，在DMD小鼠模型中，RyR 2磷酸化的抑制可以通过减少RyR 2氧化来防止SR Ca 2+泄漏。共聚焦钙离子成像和单个RyR 2通道记录显示，抑制S2808或S2814磷酸化和抑制氧化可以使mdx小鼠RyR 2活性正常化。此外，蛋白质印迹显示，在S2808或S2814处RyR 2磷酸化的遗传抑制减少RyR 2氧化。通过抑制RyR 2磷酸化或ROS清除剂2-巯基丙酰甘氨酸（MPG），mdx小鼠肌细胞中活性氧（ROS）的产生减少。最后，显示mdx小鼠中的ROS产生与RyR 2介导的SR Ca 2+泄漏的活性成比例，并且可能由Nox 2产生。mdx小鼠心脏中ROS产生的增加驱动了心功能障碍的进展。RyR 2磷酸化的抑制可以部分地通过减少RyR 2氧化来抑制mdx小鼠心脏中的SR Ca 2+渗漏。
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) Ca2+ 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)/Ca2+ release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca2+ leak by reducing RyR2 oxidation. Confocal Ca2+ 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 Ca2+ leak, and likely generated by Nox2. Increased ROS production in the hearts of mdx mice drives the progression of cardiac dysfunction. Inhibition of RyR2 phosphorylation can suppress SR Ca2+ leak in mdx mouse hearts in part by reducing RyR2 oxidation.