Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
Heart Rhythm. 2013 Apr;10(4):592-9. doi: 10.1016/j.hrthm.2012.12.016. Epub 2012 Dec 12.
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.
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.
Programmed electrical stimulation was performed on anesthetized mice and confocal imaging of Ca(2+) release events in isolated ventricular myocytes.
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.
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.
室性心动过速（VT）是杜氏肌营养不良症（DMD）患者死亡的第二大常见原因。最近的研究表明，通过 2 型兰尼碱受体（RyR2）增强肌质网（SR）Ca2+泄漏是 DMD 的 mdx 小鼠模型中 VT 的原因。然而，SR Ca2+泄漏和 VT 诱导的信号机制尚不清楚。
测试增强的 RyR2 上 Ca2+/钙调蛋白依赖性蛋白激酶 II（CaMKII）磷酸化是否是 mdx 小鼠 SR Ca2+泄漏和 VT 诱导的基础。
对麻醉小鼠进行程控电刺激，并对分离的心室肌细胞中的 Ca2+释放事件进行共焦成像。
程控电刺激揭示了 mdx 小鼠可诱导 VT，该 VT 可被 CaMKII 抑制或 RyR2 的 S2814A 突变所抑制。与野生型小鼠相比，mdx 小鼠的肌细胞显示出更多的 Ca2+火花和 Ca2+波，特别是在更快的起搏速率下。心律失常性 Ca2+波可被 CaMKII 抑制，但不能被蛋白激酶 A 抑制。此外，RyR2 的 S2814A 突变但不是 S2808A 突变抑制了 mdx 小鼠肌细胞中的自发性 Ca2+波。
CaMKII 阻断和 RyR2-S2814 磷酸化的遗传抑制可防止 DMD 小鼠模型中的 VT 诱导。在 mdx 小鼠的心室肌细胞中，自发的 Ca2+火花和 Ca2+波可被 CaMKII 抑制或 RyR2 的 S2814A 突变抑制。因此，抑制 CaMKII 诱导的 SR Ca2+泄漏可能是防止无心力衰竭的 DMD 患者心律失常的新策略。
