Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation
Joint Authors
Li, Baoxin
Liu, Yan
Xu, Xueqi
Zhang, Yuhao
Li, Mingzhu
Guo, Jiamengyi
Yan, Caichuan
Wang, Fang
Li, Yuexin
Ding, Yunqi
Fan, Pan
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-17, 17 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2020-01-23
Country of Publication
Egypt
No. of Pages
17
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Liu, Yan& Xu, Xueqi& Zhang, Yuhao& Li, Mingzhu& Guo, Jiamengyi& Yan, Caichuan…[et al.]. 2020. Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation. Oxidative Medicine and Cellular Longevity،Vol. 2020, no. 2020, pp.1-17.
https://search.emarefa.net/detail/BIM-1204326
Modern Language Association (MLA)
Liu, Yan…[et al.]. Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation. Oxidative Medicine and Cellular Longevity No. 2020 (2020), pp.1-17.
https://search.emarefa.net/detail/BIM-1204326
American Medical Association (AMA)
Liu, Yan& Xu, Xueqi& Zhang, Yuhao& Li, Mingzhu& Guo, Jiamengyi& Yan, Caichuan…[et al.]. Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation. Oxidative Medicine and Cellular Longevity. 2020. Vol. 2020, no. 2020, pp.1-17.
https://search.emarefa.net/detail/BIM-1204326
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1204326