Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy (Publication with Expression of Concern)
Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy (Publication with Expression of Concern)
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DOI：
10.1161/01.cir.0000027583.73268.e7
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发表时间：
2002-09-03
期刊：
影响因子：
37.8
通讯作者：
Anderson, ME
中科院分区：
文献类型：
--
作者：
Wu, YJ;Temple, J;Anderson, ME
背景：钙调蛋白激酶（CaMK） 11在复极延长的细胞模型中与心律失常机制有关。CaMKII上调和复极延长是心肌病的普遍特征，但CaMKII在心肌病心律失常中的作用尚不清楚。方法和结果：我们研究了一种由转基因（TG）过表达CaMKIV组成活性形式引起的小鼠心肌肥大模型，该CaMKIV也增加了内源性CaMKII活性。心电图遥测TG小鼠在基线时比野生型（WT）小鼠有更多的心律失常，异丙肾上腺素还会增加心律失常。靶向内源性CaMKIL的抑制剂显著抑制心律失常，TG小鼠比WT小鼠具有更长的QT间期和动作电位持续时间，TG心肌细胞有频繁的早期后去极化（EADs），这是引发心律失常的一种假设机制。在注射异丙肾上腺素前和注射后，WT细胞中不存在EAD，而TG小鼠的EAD频率不受异丙肾上腺素的影响。l型Ca2+通道（LTTCs）可激活EADs，且异丙肾上腺素前后TG心肌细胞LTCC打开概率（Po）显著高于WT心肌细胞。CaMKII抑制肽平衡TG和WT LTCC Po并消除EADs，而Na+/Ca2+交换电流的肽拮抗剂（也被假设支持EADs）无效。结论：这些发现支持了CaMKII是体内心肌肥厚的促心律失常信号分子的假设。细胞研究指出EAD是心律失常的触发机制，但表明β -肾上腺素能刺激后心律失常的增加与EAD频率的增加无关。
Background-Calmodulin kinase (CaMK) 11 is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown.Methods and Results-We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKIL TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective.Conclusions-These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after beta-adrenergic stimulation is independent of enhanced EAD frequency.