Estradiol protection against toxic effects of catecholamine on electrical properties in human-induced pluripotent stem cell derived cardiomyocytes.

Abstract

BACKGROUND AND PURPOSE:

Previous studies revealed that Takotsubo cardiomyopathy (TTC), a transient disorder of ventricular dysfunction affecting predominantly postmenopausal women, is associated with acquired long QT syndrome and arrhythmias, but the exact pathophysiologic mechanism is unknown. Our aim is to investigate the electrophysiological mechanism for QT-prolongation in TTC-patients by using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

METHODS:

hiPSC-CMs, which were generated from human skin fibroblasts of three healthy donors, were treated by estradiol (10μM for one week) and a toxic concentration of isoprenaline (Iso, 1mM for 2h). Patch clamp techniques, qPCR and fluorescence-activated cell sorting (FACS) were employed for the study.

KEY RESULTS:

Iso enhanced late INa and suppressed Ito and thus prolonged the action potential duration (APD), suggesting possible reasons for arrhythmias in TTC. Iso elevated the production of reactive oxygen species (ROS). N-acetylcystein (1mM), a ROS-blocker, abolished the effects of Iso on late INa and Ito. H2O2 (100μM) mimicked Iso effects on late INa and Ito. These data indicate that the effects of Iso were mediated by ROS. Metoprolol (1mM), a beta-blocker, prevented the effects of Iso on late INa and APD, confirming the adrenoceptor-dependent effects of Iso. Estradiol treatment prevented the APD-prolongation, attenuated the enhancement of INa, diminished the reduction of Ito, suppressed ROS-production induced by Iso and reduced the expression levels of adrenoceptors, suggesting protective effects of estragon against toxic effects of catecholamine.

CONCLUSIONS:

Estradiol has protective effects against catecholamine excess and hence reduction in estrogen level may increase the risk of acquired long QT syndrome in TTC.

• Authors: Ibrahim El-Battrawy, Zhihan Zhao, Huan Lan, Jan-Dierk Schünemann, Katherine Sattler, Fanis Buljubasic, Bence Patocskai, Xin Li, Gökhan Yücel, Siegfried Lang, Daniel Nowak, Lukas Cyganek, Karen Bieback, Jochen Utikal, Wolfram-Hubertus Zimmermann, Ursula Ravens, Thomas Wieland, Martin Borggrefe, Xiao-Bo Zhou, Ibrahim Akin
• Journal: International journal of cardiology (Int J Cardiol) Vol. 254 Pg. 195-202 (03 01 2018) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 29407091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Catecholamines
• Reactive Oxygen Species
• Estradiol

Topics

• Action Potentials (drug effects, physiology)
• Catecholamines (toxicity)
• Cells, Cultured
• Cytoprotection (drug effects, physiology)
• Estradiol (pharmacology, therapeutic use)
• Fibroblasts (drug effects, physiology)
• Humans
• Induced Pluripotent Stem Cells (drug effects, physiology)
• Long QT Syndrome (drug therapy, physiopathology)
• Myocytes, Cardiac (drug effects, physiology)
• Reactive Oxygen Species (metabolism)
• Takotsubo Cardiomyopathy (drug therapy, physiopathology)