Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.
Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.
复制标题
芸香碱靶向 hERG 通道并参与调节导致室性心律失常的电生理特性。
DOI：
10.1111/jcmm.16292
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发表时间：
2021-06
影响因子：
5.3
通讯作者：
Li BX
中科院分区：
文献类型：
--
作者：
Zhan G;Wang F;Ding YQ;Li XH;Li YX;Zhao ZR;Li JX;Liu Y;Zhao X;Yan CC;Li BX
药物介导或医疗条件介导的HERG功能障碍是获得性长QT综合征(AcLQTS)的主要原因，该综合征易导致室性心律失常(VA)和猝死。许多中草药，尤其是生物碱，在临床应用中存在心律失常的风险。这种不良反应背后的特有机制往往与心脏HERG通道的抑制有关。本研究旨在评价吴茱萸次碱(RUT)对HERG通道的有效作用。用HERG-HEK293细胞研究RUT对HERG通道的影响及其机制。用膜片钳技术测量HERG电流(IhERG)。Western印迹分析蛋白质水平，免疫沉淀法测定Sp1的磷酸化。应用光学标测和程控电刺激评价心脏电生理活动，如动作电位时程、QT/QTc值、心律失常发生率、相位奇异性(PSS)和主频(Df)。我们的结果表明，RUT通过瞬间与HERG通道的F656和Y652氨基酸残基结合，加速通道失活，并被困在通道中，从而降低了IhERG。与RUT共同孵育24小时可降低HERG通道的水平，同时抑制细胞核内Sp1的表达。机制上，RUT通过PI3K/Akt途径降低Sp1的苏氨酸(Thr)/酪氨酸(Tyr)磷酸化，调节HERG通道的表达。基于细胞的模型不能完全揭示心律失常的病理过程。活体实验发现，给予RUT 2周后，豚鼠心脏QT/QT间期延长，室颤诱发率增加。导致心律失常发生率增加的关键原因是APD90和APD50延长，DF增加，PSS数目增加，早期后除极(EADS)发生率增加。综上所述，本研究的结果表明，RUT可以通过瞬时通过F656和Y652与HERG通道结合来降低IhERG。而从RUT(孵育24小时)的长期效应来看，PI3K/Akt/Sp1轴可能在HERG通道的调节中起着至关重要的作用。重要的是，车辙引起的电生理特性的改变是VA发生的主要原因。
Drug‐mediated or medical condition‐mediated disruption of hERG function accounts for the main cause of acquired long‐QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG‐HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG) was measured by patch‐clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell‐based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after‐depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long‐term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.
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影响因子：
168.9
作者：
Viskin, S
通讯作者：
Viskin, S
影响因子：
37.8
作者：
Mandapati, R;Asano, Y;Jalife, J
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2
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作者：
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