Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia
Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia
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DOI：
10.1016/j.hrthm.2019.10.016
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发表时间：
2020-03-01
期刊：
影响因子：
5.5
通讯作者：
Hund, Thomas J.
中科院分区：
文献类型：
--
作者：
Greer-Short, Amara;Musa, Hassan;Hund, Thomas J.
背景心房颤动（AF）是最常见的心律失常类型。异常的心房肌细胞Ca 2+处理促进异常的膜兴奋性和重构，这对心房肌的发生是重要的。导致正常心房肌细胞Ca 2+稳态丧失的分子事件顺序尚未确定。晚Na+电流目的探讨房颤患者心房肌细胞内Ca 2 +/钙调素依赖性激酶II（CaMKII）的活性是否与Na（V）1.5上Ser 571的磷酸化有关，从而导致心房肌细胞内Ca 2+循环异常，电生理改变，方法心房肌细胞电生理学，Ca 2+处理，在野生型和Scn 5a基因敲入小鼠中研究了表达拟磷酸化（S571 E）或磷酸化抗性（S571 A）Na（V）的小鼠的心律失常易感性。结果S571 E小鼠心房肌细胞的INa、L和动作电位时程均增加，肾上腺素能应激后延迟后除极增加，而S571 A小鼠心房肌细胞则无此现象。与野生型相比，S571 E心房肌细胞中的Ca 2+火花和波的频率增加。S571 E小鼠肾上腺素能应激和AF诱发的心房事件增加。孤立的S571 E心房更容易发生自发性心房事件，通过抑制肌浆网Ca 2+释放、CaMKII或Na+/Ca 2+交换器来消除。磷酸化Na（V）1.5在Ser 571和自磷酸化CaMK Ⅱ的表达增加心房样本从人类AF patient.CONCLUSION本研究确定CaMK Ⅱ依赖性调节Na（V）1.5作为一个重要的上游事件在钙处理缺陷和异常冲动的产生在设置AF。
BACKGROUND Atrial fibrillation (AF) is the most common type of arrhythmia. Abnormal atrial myocyte Ca2+ handling promotes aberrant membrane excitability and remodeling that are important for atrial arrhythmogenesis. The sequence of molecular events leading to loss of normal atrial myocyte Ca2+ homeostasis is not established. Late Na+ current (I-Na,I-L) is increased in atrial myocytes from AF patients together with an increase in activity of Ca2+/calmodulin-dependent kinase II (CaMKII).OBJECTIVE The purpose of this study was to determine whether CaMKII-dependent phosphorylation at Ser571 on Na(V)1.5 increases atrial INa,L, leading to aberrant atrial Ca2+ cycling, altered electrophysiology, and increased AF risk.METHODS Atrial myocyte electrophysiology, Ca2+ handling, and arrhythmia susceptibility were studied in wild-type and Scn5a knock-in mice expressing phosphomimetic (S571E) or phosphore-sistant (S571A) Na(V)1.5 at Ser571.RESULTS Atrial myocytes from S571E but not S571A mice displayed an increase in INa, L and action potential duration, and with adrenergic stress have increased delayed afterdepolarizations. Frequency of Ca2+ sparks and waves was increased in S571E atrial myocytes compared to wild type. S571E mice showed an increase in atrial events induced by adrenergic stress and AF inducibility in vivo. Isolated S571E atria were more susceptible to spontaneous atrial events, which were abrogated by inhibiting sarcoplasmic reticulum Ca2+ release, CaMKII, or the Na+/Ca2+ exchanger. Expression of phospho-Na(V)1.5 at Ser571 and autophosphorylated CaMKII were increased in atrial samples from human AF patients.CONCLUSION This study identified CaMKII-dependent regulation of Na(V)1.5 as an important upstream event in Ca2+ handling defects and abnormal impulse generation in the setting of AF.