Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca(2+)-calmodulin-dependent protein kinase II.
Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca(2+)-calmodulin-dependent protein kinase II.
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DOI：
10.1016/j.yjmcc.2010.03.013
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发表时间：
2010-07
影响因子：
5
通讯作者：
Shannon TR
中科院分区：
文献类型：
--
作者：
Curran J;Brown KH;Santiago DJ;Pogwizd S;Bers DM;Shannon TR
心脏兰尼碱受体（RyR）依赖性舒张期SR Ca漏增加存在于心力衰竭和肾上腺素能紧张度高的情况下。增加SR的Ca泄漏可导致自发Ca波（SCaW）的形成。SCaW激活内向Na/Ca交换器（NCX）电流，引起延迟后除极（DAD），可能导致心律失常。在这里，我们研究SCaW心室肌细胞分离失败和健康的兔子心脏。来自健康心脏的心肌细胞在基线条件下没有表现出SCaW，而暴露于异丙肾上腺素（ISO）的心肌细胞中有43%没有表现出SCaW。这种ISO诱导的活性增加被逆转抑制钙调蛋白依赖性蛋白激酶II（CaMKII）由KN 93。H89对cAMP依赖性蛋白激酶（PKA）的抑制作用未观察到。用毛喉素处理的心肌细胞中，50%显示SCaW活性，这归因于SR Ca负荷（[Ca]SRT）相对于对照的大幅增加。在相似的[Ca]SRT（121 µM）下，ISO + KN 93处理的心肌细胞的SCaWs显著少于ISO或ISO + H89处理的心肌细胞（分别为0.2±0.28 vs. 1.1±0.28和1.29±0.39 SCaWs cell−1）。在从衰竭心脏分离的肌细胞中，ISO诱导产生SCaW的细胞百分比相对于基线增加（74%对11%），而[Ca]SRT没有增加。抑制CaMKII逆转了这种效应（14%）。在相似的[Ca]SRT（71 µM）下，用ISO或ISO加H89处理的肌细胞与未处理的相比具有显著更多的SCaW/细胞（分别为2.5±0.5; 1.6±0.7 vs. 0.36±0.3）。ISO加KN 93处理完全消除了这种影响。有证据表明，在健康和衰竭的心肌细胞中SCaW活性的ISO依赖性增加是CaMK II依赖性的，暗示CaMK II参与了心肌发生。
Increased cardiac ryanodine receptor (RyR)-dependent diastolic SR Ca leak is present in heart failure and in conditions when adrenergic tone is high. Increasing Ca leak from the SR could result in spontaneous Ca wave (SCaW) formation. SCaWs activate the inward Na/Ca exchanger (NCX) current causing a delayed afterdepolarization (DAD), potentially leading to arrhythmia. Here we examine SCaWs in ventricular myocytes isolated from failing and healthy rabbit hearts. Myocytes from healthy hearts did not exhibit SCaWs under baseline conditions versus 43% of those exposed to isoproterenol (ISO). This ISO-induced increase in activity was reversed by inhibition of Ca-calmodulin-dependent protein kinase II (CaMKII) by KN93. Inhibition of cAMP-dependent protein kinase (PKA) by H89 had no observed effect. Of myocytes treated with forskolin 50% showed SCaW activity, attributable to a large increase in SR Ca load ([Ca]SRT) versus control. At similar [Ca]SRT (121 µM) myocytes treated with ISO plus KN93 had significantly fewer SCaWs versus those treated with ISO or ISO plus H89 (0.2±0.28 vs. 1.1±0.28 & 1.29±0.39 SCaWs cell−1, respectively). In myocytes isolated from failing hearts ISO induced an increase in the percentage of cells generating SCaWs vs. baseline (74% vs. 11%) with no increase in [Ca]SRT. Inhibiting CaMKII reversed this effect (14%). At similar [Ca]SRT (71 µM) myocytes treated with ISO or ISO plus H89 had significantly more SCaWs per cell vs. untreated (2.5±0.5; 1.6±0.7 vs. 0.36±0.3, respectively). Treatment with ISO plus KN93 completely abolished this effect. The evidence suggests the ISO-dependent increase in SCaW activity in both healthy and failing myocytes is CaMKII-dependent, implicating CaMKII in arrhythmogenesis.
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