Estrogen contributes to gender differences in mouse ventricular repolarization.
Estrogen contributes to gender differences in mouse ventricular repolarization.
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DOI：
10.1161/circresaha.108.190041
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发表时间：
2009-08-14
影响因子：
20.1
通讯作者：
Eghbali M
中科院分区：
文献类型：
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作者：
Saito T;Ciobotaru A;Bopassa JC;Toro L;Stefani E;Eghbali M
快速瞬态向外 K+ (Ito,f) 和超快速延迟整流 K+ 电流（IKur 或 IK,slow）有助于小鼠心脏复极。针对这些潮流的性别研究报告了相互矛盾的结果。这些研究中缺失的一个关键信息是动物的发情期。我们决定重新审视 K+ 电流中与性别相关的差异，同时考虑到雌性的发情阶段。我们假设动情周期中雌激素水平的变化可能在确定心室复极所需的 K+ 电流密度方面发挥作用。发情期雄性的峰值总 K+ 电流（IK，总）密度（pA/pF，+40 mV）（48.6±3.0）远高于雌性（27.2±2.3），但发情间期 2 时则不然（39.1±3.4）。在这一变化的基础上，雌性发情期的 Ito,f 和 IK,slow 低于雄性和发情间期 2（IK,slow：雄性 21.9±1.8，发情期 14.6±0.6，发情期 2 20.3±1.4；Ito,f：雄性 26.8±1.9，发情期 14.9±1.6，发情间期 -2 22.1±2.1）。 IK降低，发情缓慢仅由于IK，slow1降低，而没有IK，slow2变化。卵巢切除小鼠的雌激素治疗降低了 IK,total (46.4±3.0 至 28.4±1.6)、Ito,f (26.6±1.6 至 12.8±1.0) 和 IK,slow (22.2±1.6 至 17.2±1.4)。发情期的 Kv4.3 和 Kv1.5（分别是 Ito,f 和 IK,slow 的基础）的转录水平低于发情间期 2 和雄性。在卵巢切除小鼠中，雌激素治疗导致 Kv4.3 和 Kv1.5 转录本下调，但不下调 Kv4.2、KChIP2 和 Kv2.1 转录本。高雌激素条件下 K+ 电流的减少与动作电位持续时间和校正 QT 间期的延长相关。雌激素下调 Kv4.3 和 Kv1.5 转录本是定义小鼠心室复极性别相关差异的机制之一。
Fast-transient outward K+ (Ito,f) and ultra-rapid delayed rectifier K+ currents (IKur or IK,slow) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. One key missing piece information in these studies is the animals’ estral stage. We decided to revisit gender-related differences in K+ currents, taking into consideration the females’ estral stage. We hypothesized that changes in estrogen levels during the estral cycle could play a role in determining the densities of K+ currents underlying ventricular repolarization. Peak total K+ current (IK,total) densities (pA/pF, at +40 mV) were much higher in males (48.6±3.0) than in females at estrus (27.2±2.3) but not at diestrus-2 (39.1±3.4). Underlying this change, Ito,f and IK,slow were lower in females at estrus vs males and diestrus-2 (IK,slow: male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; Ito,f: male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). The lower IK,slow in estrus was only due to IK,slow1 reduction without changes of IK,slow2. Estrogen treatment of ovariectomized mice decreased IK,total (46.4±3.0 to 28.4±1.6), Ito,f (26.6±1.6 to 12.8±1.0) and IK,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying Ito,f and IK,slow, respectively) were lower in estrus vs. diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5, but not Kv4.2, KChIP2 and Kv2.1 transcripts. K+ current reduction in high estrogenic conditions were associated with prolongation of the action potential duration and corrected QT interval. Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization.