Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy
Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy
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DOI：
10.1073/pnas.0908540107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Lacampagne, Alain
中科院分区：
文献类型：
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作者：
Fauconnier, Jeremy;Thireau, Jerome;Lacampagne, Alain
Duchenne肌营养不良症(DMD)患者有进行性扩张型心肌病伴致死性心律失常。电和功能异常被归因于心脏纤维化；然而，在没有明确的心脏组织病理学的情况下，电异常也可能发生。在此，我们发现在DMD的MDX小鼠模型中，心肌肌浆网(SR)钙释放通道/兰尼定受体(RyR2)的结构和功能发生了重构。来自MDX心脏的RyR2被S亚硝化并耗尽钙化蛋白2(FKBP12.6)，导致RyR2通道“泄漏”和舒张期SR钙泄漏。用钙通道稳定剂S107(“rycal”)抑制RyR2复合体中钙调素2的耗竭，可抑制肌浆网钙离子泄漏，抑制心肌细胞的异常去极化，防止体内心律失常。这提示，由于通道的S亚硝化和钙通道复合体中钙调蛋白2的耗竭，通过RyR2的舒张期肌浆网钙离子泄漏可能触发心律失常。RyR2介导的舒张期SR钙渗漏正常化可防止DMD患者发生致命性突发性心律失常。
Patients with Duchenne muscular dystrophy (DMD) have a progressive dilated cardiomyopathy associated with fatal cardiac arrhythmias. Electrical and functional abnormalities have been attributed to cardiac fibrosis; however, electrical abnormalities may occur in the absence of overt cardiac histopathology. Here we show that structural and functional remodeling of the cardiac sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from mdx hearts were S-nitrosylated and depleted of calstabin2 (FKBP12.6), resulting in "leaky" RyR2 channels and a diastolic SR Ca2+ leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the Ca2+ channel stabilizer S107 ("rycal") inhibited the SR Ca2+ leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR Ca2+ leak via RyR2 due to S-nitrosylation of the channel and calstabin2 depletion from the channel complex likely triggers cardiac arrhythmias. Normalization of the RyR2-mediated diastolic SR Ca2+ leak prevents fatal sudden cardiac arrhythmias in DMD.