Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing.
Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing.
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DOI：
10.1016/j.hrthm.2012.07.014
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发表时间：
2012-11
期刊：
影响因子：
5.5
通讯作者：
Rosen, Michael R.
中科院分区：
文献类型：
--
作者：
Oezgen, Nazira;Lu, Zhongju;Boink, Gerard J. J.;Lau, David H.;Shlapakova, Iryna N.;Bobkov, Yevgeniy;Danilo, Peter, Jr.;Cohen, Ira S.;Rosen, Michael R.
犬心脏左心室起搏（LVP）改变心室激动，导致瞬时外向钾电流Ito降低、心外膜动作电位切迹丢失和T波向量位移（TVD）。这些复极变化，称为心脏记忆，是由局部增加的血管紧张素II（AngII）水平启动的。在HEK 293细胞中，其中Kv4.3和KChIP 2（对Ito有贡献的通道亚基）与AngII受体1（AT 1 R）过表达，AngII诱导Ito降低，这是Kv4.3/KChIP 2/AT 1 R大分子复合物内化的结果。我们测试的假设，在犬心脏原位，2小时LVP诱导的膜KChIP 2，AT 1 R和Ito的减少是通过阻断亚基贩运。我们使用标准的电生理学、生物物理学和生物化学方法研究了4组犬：1）假手术组，2）2 h LVP组，3）LVP+秋水仙碱（微管破坏剂）组和4）LVP+氯沙坦（AT 1 R阻断剂）组。LVP的TVD显著大于Shams，并被秋水仙碱或氯沙坦抑制。心外膜活检显示LVP后膜KChIP 2和AT 1 R蛋白显著降低，但假手术治疗后无此现象，秋水仙碱或氯沙坦可预防这些降低。秋水仙碱而不是氯沙坦显着减少微管聚合。在离体心室肌细胞中，AngII诱导的Ito降低和动作电位切迹丢失被秋水仙碱阻断。LVP诱导的KChIP 2在质膜中的减少依赖于AngII介导的途径和完整的微管状态。Ito和动作电位缺口的损失似乎来自AngII启动的通道亚基的贩运。
Left ventricular pacing (LVP) in canine heart alters ventricular activation leading to reduced transient outward potassium current, Ito, loss of the epicardial action potential notch, and T wave vector displacement (TVD). These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to Ito, are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in Ito as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex. We tested the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R and Ito are prevented by blocking subunit trafficking. We used standard electrophysiologic, biophysical and biochemical methods to study 4 groups of dogs: 1) Sham, 2) 2h LVP, 3) LVP+colchicine (microtubule disrupting agent) and 4) LVP+losartan (AT1R blocker). TVD was significantly greater in LVP than Shams and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in membrane KChIP2 and AT1R protein after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes AngII-induced Ito reduction and loss of action potential notch were blocked by colchicine. LVP-induced reduction of KChIP2 in plasma light membranes depends on an AngII-mediated pathway and intact microtubular status. Loss of Ito and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits.
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