Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval.
Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval.
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KCNE3 的异位表达会加速心脏复极并缩短 QT 间期。
DOI：
10.1172/jci15062
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Marbán,Eduardo
中科院分区：
文献类型：
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作者：
Mazhari,Reza;Nuss,HBradley;Armoundas,AntonisA;Winslow,RaimondL;Marbán,Eduardo
调节亚基KCNE 3（E3）与上皮细胞中的KCNQ 1（Q1）相互作用，调节其活化动力学并增加电流密度。由于E3在心脏中表达较弱，我们推测E3在心肌细胞中的异位表达可能通过与Q1相互作用并增加延迟整流电流（IK）而延长动作电位时程（APD）。因此，我们在中国仓鼠卵巢细胞中瞬时共表达E3、Q1和KCNE 1（E1），发现E3共表达使外向电流增加≥ -80 mV，并加速激活。然后，我们研究了心脏电生理的变化后，注射腺病毒表达的E3到豚鼠的左心室腔。72小时后，心电图的校正QT间期缩短了约10%。与对照组相比，E3转导细胞的APD减少了3倍以上，而E-4031不敏感的IKand激活动力学显著增强。基于定量建模的透壁心脏节段，我们表明，QT间期缩短的程度观察到的结果从电紧张性相互作用在面对有限的转导效率和E3的异质性转导实际上可能会增强心律失常。只要能够实现调节亚基的相当均匀的异位心室表达，这种方法可能有助于增强复极和治疗长QT综合征。
Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density. Since E3 is expressed weakly in the heart, we hypothesized that ectopic expression of E3 in cardiac myocytes might abbreviate action potential duration (APD) by interacting with Q1 and augmenting the delayed rectifier current (IK). Thus, we transiently coexpressed E3 with Q1 and KCNE1 (E1) in Chinese hamster ovary cells and found that E3 coexpression increased outward current at potentials by ≥ –80 mV and accelerated activation. We then examined the changes in cardiac electrophysiology following injection of adenovirus-expressed E3 into the left ventricular cavity of guinea pigs. After 72 hours, the corrected QT interval of the electrocardiogram was reduced by ∼10%. APD was reduced by >3-fold in E3-transduced cells relative to controls, while E-4031–insensitive IKand activation kinetics were significantly augmented. Based on quantitative modeling of a transmural cardiac segment, we demonstrate that the degree of QT interval abbreviation observed results from electrotonic interactions in the face of limited transduction efficiency and that heterogeneous transduction of E3 may actually potentiate arrhythmias. Provided that fairly homogeneous ectopic ventricular expression of regulatory subunits can be achieved, this approach may be useful in enhancing repolarization and in treating long QT syndrome.