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Alpha 1-adrenoceptor signalling contributes to toxic effects of catecholamine on electrical properties in cardiomyocytes

This study aimed to investigate possible roles and underlying mechanisms of alpha-adrenoceptor coupled signalling for the pathogenesis of Takotsubo syndrome (TTS).Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with a toxic concentration of epinephrine (Epi, 0.5 m...

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Main Authors: Huang, Mengying (Author) , Fan, Xuehui (Author) , Yang, Zhen (Author) , Cyganek, Lukas (Author) , Li, Xin (Author) , Yücel, Gökhan (Author) , Lan, Huan (Author) , Li, Yingrui (Author) , Wendel, Angela (Author) , Lang, Siegfried (Author) , Bieback, Karen (Author) , El-Battrawy, Ibrahim (Author) , Zhou, Xiao-Bo (Author) , Akın, Ibrahim (Author) , Borggrefe, Martin (Author)
Format: Article (Journal)
Language:English
Published: July 2021
In: Europace
Year: 2021, Volume: 23, Issue: 7, Pages: 1137-1148
ISSN:1532-2092
DOI:10.1093/europace/euab008
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/europace/euab008
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Author Notes:Mengying Huang, Xuehui Fan, Zhen Yang, Lukas Cyganek, Xin Li, Goekhan Yuecel, Huan Lan, Yingrui Li, Angela Wendel, Siegfried Lang, Karen Bieback, Ibrahim El-Battrawy, Xiaobo Zhou, Ibrahim Akin and Martin Borggrefe
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Summary:This study aimed to investigate possible roles and underlying mechanisms of alpha-adrenoceptor coupled signalling for the pathogenesis of Takotsubo syndrome (TTS).Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with a toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) to mimic the setting of TTS. Patch-clamp technique, polymerase chain reaction (PCR) and Fluorescence-activated cell sorting (FACS) were employed for the study. High concentration Epi suppressed the depolarization velocity, prolonged duration of action potentials and induced arrhythmic events in hiPSC-CMs. The Epi effects were attenuated by an alpha-adrenoceptor blocker (phentolamine), suggesting involvement of alpha-adrenoceptor signalling in arrhythmogenesis related to QT interval prolongation in the setting of TTS. An alpha 1-adrenoceptor agonist (phenylephrine) but not an alpha 2-adrenoceptor agonist (clonidine) mimicked Epi effects. Epi enhanced ROS production, which could be attenuated by the alpha- adrenoceptor blocker. Treatment of cells with H2O2 (100 µM) mimicked the effects of Epi on action potentials and a reactive oxygen species (ROS)-blocker (N-acetyl-I-cysteine, 1 mM) prevented the Epi effects, indicating that the ROS signalling is involved in the alpha-adrenoceptor actions. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases were involved in alpha 1-adrenoceptor signalling. A protein kinase C (PKC) blocker suppressed the effects of Epi, phenylephrine and ROS as well, implying that PKC participated in alpha 1-adrenoceptor signalling and acted as a downstream factor of ROS. The abnormal action potentials resulted from alpha 1-adrenoceptor activation-induced dysfunctions of ion channels including the voltage-dependent Na+ and L-type Ca2+ channels.Alpha 1-adrenoceptor signalling plays important roles for arrhythmogenesis of TTS. Alpha-adrenoceptor blockers might be clinically helpful for treating arrhythmias in patients with TTS.
Item Description:Published: 19 January 2021
Gesehen am 24.06.2022
Physical Description:Online Resource
ISSN:1532-2092
DOI:10.1093/europace/euab008

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