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Nucleoside Diphosphate Kinase B Contributes to Arrhythmogenesis in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy

1
First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
2
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, 68167 Mannheim, Germany
3
Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, 646000 Luzhou, China
4
Experimental Pharmacology Mannheim, European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
5
Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
*
Author to whom correspondence should be addressed.
Akin and Borggrefe and Wieland share senior authorship.
J. Clin. Med. 2020, 9(2), 486; https://doi.org/10.3390/jcm9020486
Received: 8 January 2020 / Revised: 30 January 2020 / Accepted: 5 February 2020 / Published: 10 February 2020
(This article belongs to the Section Cardiology)
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare, inheritable cardiac disorder characterized by ventricular tachyarrhythmias, progressive loss of cardiomyocytes with fibrofatty replacement and sudden cardiac death. The exact underlying mechanisms are unclear. Methods: This study investigated the possible roles of nucleoside diphosphate kinase B (NDPK-B) and SK4 channels in the arrhythmogenesis of ARVC by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results: In hiPSC-CMs from a patient with ARVC, the expression levels of NDPK-B and SK4 channels were upregulated, the cell automaticity was increased and the occurrence rate of arrhythmic events was enhanced. Recombinant NDPK-B applied into hiPSC-CMs from either healthy donors or the patient enhanced SK4 channel current (ISK4), cell automaticity and the occurrence of arrhythmic events, whereas protein histidine phosphatase 1 (PHP-1), a counter actor of NDPK-B, prevented the NDPK-B effect. Application of PHP-1 alone or a SK4 channel blocker also reduced cell automaticity and arrhythmic events. Conclusion: This study demonstrated that the elevated NDPK-B expression, via activating SK4 channels, contributes to arrhythmogenesis in ARVC, and hence, NDPK-B may be a potential therapeutic target for treating arrhythmias in patients with ARVC. View Full-Text
Keywords: arrhythmogenic right ventricular cardiomyopathy; human-induced pluripotent stem cell-derived cardiomyocyte; nucleoside diphosphate kinase; SK4 channel; arrhythmia arrhythmogenic right ventricular cardiomyopathy; human-induced pluripotent stem cell-derived cardiomyocyte; nucleoside diphosphate kinase; SK4 channel; arrhythmia
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MDPI and ACS Style

Buljubasic, F.; El-Battrawy, I.; Lan, H.; Lomada, S.K.; Chatterjee, A.; Zhao, Z.; Li, X.; Zhong, R.; Xu, Q.; Huang, M.; Liao, Z.; Lang, S.; Cyganek, L.; Zhou, X.; Wieland, T.; Borggrefe, M.; Akin, I. Nucleoside Diphosphate Kinase B Contributes to Arrhythmogenesis in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy. J. Clin. Med. 2020, 9, 486.

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