Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation
Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation
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硫利达嗪通过活性氧介导的 hERG 通道缺陷和 L 型钙通道激活诱导心脏毒性
DOI：
10.1155/2020/3690123
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发表时间：
2020-01
影响因子：
--
通讯作者：
Fan Pan
中科院分区：
文献类型：
--
作者：
Liu Yan;Xu Xueqi;Zhang Yuhao;Li Mingzhu;Guo Jiamengyi;Yan Caichuan;Wang Fang;Li Yuexin;Ding Yunqi;Li Baoxin;Fan Pan
硫利达嗪（THIO）是一种吩噻嗪衍生物，主要用于治疗精神障碍。然而，与该化合物应用相关的心律失常特别是QT间期延长在其引入临床实践后受到了严重关注，并且THIO诱导的心脏毒性的潜在机制尚未得到很好的定义。本研究旨在探索THIO对hERG和L型钙通道的长期影响，这两者都与QT延长的发展相关。通过膜片钳技术测量hERG电流（IhERG）和钙电流（伊卡）。蛋白质水平进行了分析，蛋白质印迹和通道分子伴侣相互作用进行了测定，通过免疫共沉淀。采用流式细胞术和激光扫描共聚焦显微镜检测细胞内活性氧的含量。我们的结果表明THIO诱导hERG通道缺陷，但不改变通道动力学。THIO促进ROS的产生并刺激内质网（ER）应激及其相关蛋白。ROS清除剂N-乙酰半胱氨酸（NAC）显着减弱THIO诱导的hERG降低，并取消ER应激标志物蛋白的上调。同时，THIO通过破坏hERG与Hsp 70的相互作用，增加了hERG通道的降解。泛素修饰后的hERG蛋白在蛋白酶体中被降解。另一方面，THIO增加了新生大鼠心室心肌细胞（NRVM）中的伊卡密度和细胞内Ca 2+（[Ca 2 +]i）。特异性CaMKII抑制剂KN-93减弱了细胞内Ca 2+超载，表明ROS介导的CaMKII激活促进了THIO诱导的钙通道激活。光学标测分析表明THIO对小鼠心脏复极化的减缓作用。THIO显着延长APD 50和APD 90，并增加早期后除极（埃兹）的发生率。在人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）中，THIO也导致APD延长。结论：THIO诱导QT间期延长的离子机制可能是hERG通道蛋白功能障碍和L型钙通道活性增强。
Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (IhERG) and the calcium current (ICa‐L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased ICa‐L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.
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影响因子：
5
作者：
Zhao Z;Fefelova N;Shanmugam M;Bishara P;Babu GJ;Xie LH
通讯作者：
Xie LH
影响因子：
12.9
作者：
Lei Yang;Jianjun Xu;Etsuko Minobe;Lifeng Yu;Rui Feng;A. Kameyama;Kazuto;Yazawa;M. Kameyama
通讯作者：
Lei Yang;Jianjun Xu;Etsuko Minobe;Lifeng Yu;Rui Feng;A. Kameyama;Kazuto;Yazawa;M. Kameyama
DOI：
--
发表时间：
2004-03
期刊：
Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology
影响因子：
--
作者：
V. Kecskeméti
通讯作者：
V. Kecskeméti
影响因子：
5.6
作者：
Ariyasu D;Yoshida H;Hasegawa Y
通讯作者：
Hasegawa Y
As2O3诱导动作电位延长的机制及利用hiPS-CM评价不同解救机制药物的解救效果
影响因子：
3.8
作者：
Yan Meng;Feng Lifang;Shi Yanhui;Wang Junnan;Liu Yan;Li Fengmei;Li Baoxin
通讯作者：
Li Baoxin