肌浆网磷蛋白敲除可阻断致心律失常性 Ca²⁺波并抑制小鼠儿茶酚胺敏感性多形性室性心动过速。
Phospholamban knockout breaks arrhythmogenic Ca²⁺ waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice.
机构信息
Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
出版信息
Circ Res. 2013 Aug 16;113(5):517-26. doi: 10.1161/CIRCRESAHA.113.301678. Epub 2013 Jul 15.
RATIONALE
Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca²⁺ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum 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.
OBJECTIVE
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 VT.
METHODS AND RESULTS
We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-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 sarcoplasmic reticulum Ca²⁺ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca²⁺ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca²⁺ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca²⁺ ATPase with 2,5-di-tert-butylhydroquinone. 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.
CONCLUSIONS
Our results demonstrate that despite severe sarcoplasmic reticulum Ca²⁺ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca²⁺ sequestration represents an effective approach for suppressing Ca²⁺-triggered arrhythmias.
理由
磷蛋白（PLN）是心肌肌浆网 Ca²⁺-ATP 酶的抑制剂。PLN 敲除（PLN-KO）增强肌浆网 Ca²⁺负荷和 Ca²⁺渗漏。相反，PLN-KO 加速 Ca²⁺摄取并终止致心律失常性自发性 Ca²⁺波（SCWs）。一个重要的问题是，PLN-KO 的这些看似矛盾的作用是加重还是保护 Ca²⁺触发的心律失常。
目的
我们研究了 PLN-KO 对心脏兰尼碱受体（RyR2）相关儿茶酚胺多形性 VT 小鼠模型中 SCWs、触发活动和应激诱导的室性心动过速（VTs）的影响。
方法和结果
我们通过将 PLN-KO 小鼠与儿茶酚胺多形性 VT 相关的 RyR2-R4496C 突变小鼠杂交，生成了 PLN 缺陷、RyR2 突变小鼠模型（PLN-/-/RyR2-R4496C+/-）。Ca²⁺成像和膜片钳记录显示，在 RyR2-R4496C+/- 心室肌细胞中，肌浆网 Ca²⁺过载时会发生全细胞传播的 SCWs 和触发活动。PLN-KO 将这些全细胞 SCWs 分割成微小波和 Ca²⁺火花，并抑制肌浆网 Ca²⁺过载引发的触发活动。重要的是，用 2,5-二叔丁基对苯二酚部分抑制肌浆网 Ca²⁺-ATP 酶可逆转 PLN-KO 的这些作用。然而，Bay K、咖啡因或 Li⁺未能将微小波转化为 PLN-/-/RyR2-R4496C+/- 心室肌细胞中的全细胞 SCWs。此外，心电图分析表明 PLN-KO 小鼠不易发生应激诱导的 VT。相反，PLN-KO 保护 RyR2-R4496C 突变小鼠免受应激诱导的 VT。
结论
我们的结果表明，尽管肌浆网 Ca²⁺渗漏严重，但 PLN-KO 仍能抑制儿茶酚胺多形性 VT 小鼠模型中的触发活动和应激诱导的 VT。这些数据表明，通过增强 Ca²⁺摄取来打断全细胞传播的 SCWs 是抑制 Ca²⁺触发心律失常的有效方法。
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