Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias.
Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias.
复制标题
通过 Cav1.2 持续增加 Ca(2+) 流入会缩短动作电位，并导致 Ca(2+) 过载引起的后除极和心律失常。
DOI：
10.1007/s00395-015-0523-4
复制
发表时间：
2016-01
影响因子：
9.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhang X;Ai X;Nakayama H;Chen B;Harris DM;Tang M;Xie Y;Szeto C;Li Y;Li Y;Zhang H;Eckhart AD;Koch WJ;Molkentin JD;Chen X
在应激和疾病心脏中，由于动作电位(AP)延长、β-肾上腺素能系统的慢性激活和分子重构而导致的钙离子内流持续增加。钙离子内流的增加通常与心肌细胞动作电位延长和心律失常有关。然而，Cav1.2活性的慢性增强对心脏电重构和心律失常的作用尚未完全确定，这是本研究的主题。用心脏特异的、可诱导的双转基因小鼠系统过表达CAV的β2a亚单位(CAvβ2a)，可产生慢性增强的CAV1.2活性。丹参总皂苷使心肌细胞L-L钙电流(ICa-L)增加，心肌细胞缩短，钙瞬变增加。DTG小鼠的心脏功能有所增强，但它们突然过早死亡。遥测心电图显示QT间期缩短。DTG心肌细胞的动作电位时程因钾电流和通道丰度显著增加而缩短。然而，DTG心肌细胞AP的缩短并不能完全抑制过量的钙内流，而使ICa-L的峰值和尾部增加。增强的ICA促进肌浆网(SR)钙超载，舒张期钙火花和波形，并增加NCX活性，导致早期和延迟后除极(EADS和DADS)的发生增加，这可能导致室性早搏和室性心动过速。同时观察到可能与房室结纤维化有关的房室传导阻滞。我们的研究提示，增加ICa-L并不一定导致AP延长，但会导致SR钙超载和房室结及心肌纤维化，从而导致细胞心律失常、心律失常和传导异常。
Persistent elevation of Ca2+ influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca2+ influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the β2a subunit of Cav (Cavβ2a). DTG myocytes had increased L-type Ca2+ current (ICa-L), myocyte shortening, and Ca2+ transients. DTG mice had enhanced cardiac performance, but they died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals. The action potential duration (APD) were shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca2+ influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca2+ overload, diastolic Ca2+ sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca2+ overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias and conduction abnormalities.