Estrogen regulation of the transient outward K+ current involves estrogen receptor α in mouse heart
Estrogen regulation of the transient outward K+ current involves estrogen receptor α in mouse heart
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DOI：
10.1016/j.yjmcc.2015.07.013
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发表时间：
2015-09-01
影响因子：
5
通讯作者：
Fiset, Celine
中科院分区：
文献类型：
--
作者：
El Gebeily, Gracia;El Khoury, Nabil;Fiset, Celine
背景和目的：我们以前的研究表明，雄激素上调心脏K+通道，缩短复极。然而，雌激素（E-2）和雌激素受体（ER）可能对各种复极化K+电流和基础离子通道的影响仍然不完全清楚。因此，我们的目标是验证是否以及如何E-2和它的ER亚型的影响这些K+ current.Methods和结果：为了检查E-2和ER对K+电流的影响，我们大幅降低E-2水平通过卵巢切除术（OVX; 74%减少CTL），并在平行，我们使用雌性小鼠缺乏ER α（ER α KO）或ER β（ER β KO）。在OVX小鼠中，结果显示与CTL相比，Ca 2+非依赖性瞬时外向K+电流（I-to）密度特异性增加35%。Western印迹显示Kv4.2和Kv4.3肌膜蛋白表达增加，而qPCR显示OVX小鼠中仅Kv4.3的mRNA表达更高。I-to的上调与较短的心室动作电位时程和QTc间期相关。在ER α KO而不是ER β KO小鼠中，Kv4.3的mRNA选择性增加。此外，当在E-2存在下培养从ER α KO和ER β KO获得的心室肌细胞时，结果显示E-2仅在ER β KO肌细胞中降低I-to密度，证实了E-2-ER α在调节I-to中的抑制作用。总之，这些结果表明，E-2通过ER α负调节I-to的密度，这突出了这种雌性激素及其α-亚型受体在调节心脏电活动中的潜在作用。(C)2015爱思唯尔有限公司版权所有。
Background and objective: We have previously shown that androgens upregulate cardiac K+ channels and shorten repolarization. However, the effects that estrogens (E-2) and estrogen receptors (ER) might have on the various repolarizing K+ currents and underlying ion channels remain incompletely understood. Accordingly, our objective was to verify whether and how E-2 and its ERs subtypes influence these K+ currents.Methods and results: In order to examine the influence of E-2 and ERs on K+ currents we drastically lowered the E-2 level through ovariectomy (OVX; 74% reduction vs CTL) and in parallel, we used female mice lacking either ER alpha (ER alpha KO) or ER beta (ER beta KO). In OVX mice, results showed a specific increase of 35% in the density of the Ca2+-independent transient outward K+ current (I-to) compared to CTL Western blots showed increase in Kv4.2 and Kv4.3 sarcolemmal protein expression while qPCR revealed higher mRNA expression of only Kv4.3 in OVX mice. This upregulation of I-to was correlated with a shorter ventricular action potential duration and QTc interval. In ER alpha KO but not ER beta KO mice, the mRNA of Kv4.3 was selectively increased. Furthermore, when ventricular myocytes obtained from ER alpha KO and ER beta KO were cultured in the presence of E-2, results showed that E-2 reduced I-to density only in ER beta KO myocytes confirming the repressive role of E-2-ER alpha in regulating I-to.Conclusion: Altogether, these results suggest that E-2 negatively regulates the density of I-to through ER alpha, this highlights a potential role for this female hormone and its alpha-subtype receptor in modulating cardiac electrical activity. (C) 2015 Elsevier Ltd. All rights reserved.