Fanis Buljubasic1,2, Ibrahim El-Battrawy1,2, Huan Lan3, Santosh K Lomada4, Anupriya Chatterjee4, Zhihan Zhao1,2, Xin Li1, Rujia Zhong1, Qiang Xu1, Mengying Huang1, Zhenxing Liao1, Siegfried Lang1,2, Lukas Cyganek2,5, Xiaobo Zhou1,2,3, Thomas Wieland2,4, Martin Borggrefe1,2, Ibrahim Akin1,2. 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, Luzhou 646000, 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.
Abstract
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.
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.
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