Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII
Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII
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DOI：
10.1016/j.ejphar.2018.12.011
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发表时间：
2019-02-05
影响因子：
5
通讯作者：
Anzai, Toshihisa
中科院分区：
文献类型：
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作者：
Kamada, Rui;Yokoshiki, Hisashi;Anzai, Toshihisa
持续性室性心律失常（SVA）导致心脏性猝死，β-肾上腺素受体阻滞剂对其有效.我们假设β-肾上腺素受体刺激引起的电生理变化和心律失常与通过增加Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）活性激活小电导钙激活钾（SK）通道密切相关。我们使用血压正常的Wistar-Kyoto（WKY）大鼠和自发性高血压大鼠（SHR）。后者作为左心室肥大的模型。我们进行了双光学映射的动作电位和Ca 2+瞬变，和异丙肾上腺素和apamin，SK通道阻滞剂，在Langendorff灌注心脏的影响进行了评估。在WKY大鼠和SHR中，异丙肾上腺素（100 nM）缩短了动作电位时程。相反，CaMKII活性增加异丙肾上腺素只在SHR。在存在异丙肾上腺素的情况下，apamin仅延长SHR的动作电位时程（n = 10，从116.6 +/- 5.05 ms至125.4 +/- 3.80 ms，P = 0.011），这被CaMKII抑制剂KN-93阻止。在两种动物中观察到异丙肾上腺素引起的Ca 2+瞬变增加和Ca 2+瞬变持续时间缩短，但不受apamin的影响。Apamin降低异丙肾上腺素诱导的SVAs和动作电位时程恢复曲线的最大斜率，特别是在SHR中。总之，β-肾上腺素受体刺激通过CaMKII依赖性激活心脏肥大中的SK通道产生促炎底物。
Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which beta- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by beta- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca2+ transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 +/- 5.05 ms to 125.4 +/- 3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca2+ transients and shortening of Ca2+ transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, beta- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.