Phospholamban knockout breaks arrhythmogenic Ca²⁺ waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice.
Phospholamban knockout breaks arrhythmogenic Ca²⁺ waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice.
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DOI：
10.1161/circresaha.113.301678
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发表时间：
2013-08-16
影响因子：
20.1
通讯作者：
Chen SR
中科院分区：
文献类型：
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作者：
Bai Y;Jones PP;Guo J;Zhong X;Clark RB;Zhou Q;Wang R;Vallmitjana A;Benitez R;Hove-Madsen L;Semeniuk L;Guo A;Song LS;Duff HJ;Chen SR
受磷蛋白（Phospholamban，PLN）是心肌肌浆网Ca ~（2+）ATP酶（SERCA 2a）的抑制剂。PLN敲除（PLN-KO）增强了肌浆网（SR）的Ca 2+负荷和Ca 2+渗漏。相反，PLN-KO加速Ca 2+螯合并中止致炎性自发Ca 2+波（SCW）。一个重要的问题是，这些看似矛盾的作用，PLN-KO加剧或保护对Ca 2+触发的心律失常。我们研究了PLN-KO对心脏ryanodine受体（RyR 2）相关的儿茶酚胺能多态性室性心动过速（CPVT）小鼠模型中SCW、触发活动和应激诱导的室性快速性心律失常（VT）的影响。我们通过将PLN-KO小鼠与CPVT相关的RyR 2-R4496 C突变小鼠杂交产生了PLN缺陷型RyR 2突变小鼠模型（PLN−/−/RyR 2-R4496 C +/−）。Ca 2+成像和膜片钳记录揭示了SR Ca 2+过载期间RyR 2-R4496 C +/−心室肌细胞中细胞范围内传播的SCW和触发活动。PLN-KO将这些细胞范围的SCW片段化为微波和Ca 2+火花，并抑制SR Ca 2+过载引起的触发活动。重要的是，通过用2，5-二叔丁基氢醌（tBHQ）部分抑制SERCA 2a来逆转PLN-KO的这些作用。然而，Bay K、咖啡因或Li+未能在PLN−/−/RyR 2-R4496 C +/−心室肌细胞中将微波转换为细胞范围的SCW。此外，ECG分析显示，PLN-KO小鼠对应激诱导的VT不敏感。相反，PLN-KO保护RyR 2-R4496 C突变小鼠免受应激诱导的VT。我们的研究结果表明，尽管严重的SR Ca 2+泄漏，PLN-KO抑制触发活动和应激诱导的VT在小鼠模型的CPVT。这些数据表明，通过增强Ca 2+螯合来打破细胞范围内传播的SCW是抑制Ca 2+触发的心律失常的有效方法。
Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a). PLN knockout (PLN-KO) enhances sarcoplasmic reticulum (SR) Ca2+ load and Ca2+ leak. Conversely, PLN-KO accelerates Ca2+ sequestration and aborts arrhythmogenic spontaneous Ca2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca2+-triggered arrhythmias. We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine receptor (RyR2)-linked catecholaminergic polymorphic ventricular tachycardia (CPVT). We generated a PLN-deficient, RyR2 mutant mouse model (PLN−/−/RyR2-R4496C+/−) by crossbreeding PLN-KO mice with CPVT-associated RyR2-R4496C mutant mice. Ca2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/− ventricular myocytes during SR Ca2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca2+ sparks, and suppressed triggered activities evoked by SR Ca2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting SERCA2a with 2,5-Di-tert-butylhydroquinone (tBHQ). However, Bay K, caffeine, or Li+ failed to convert mini-waves to cell-wide SCWs in PLN−/−/RyR2-R4496C+/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. Our results demonstrate that despite severe SR Ca2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of CPVT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca2+ sequestration represents an effective approach for suppressing Ca2+-triggered arrhythmias.