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

Fanis Buljubasic; Ibrahim El-Battrawy; Huan Lan; Santosh K Lomada; Anupriya Chatterjee; Zhihan Zhao; Xin Li; Rujia Zhong; Qiang Xu; Mengying Huang; Zhenxing Liao; Siegfried Lang; Lukas Cyganek; Xiaobo Zhou; Thomas Wieland; Martin Borggrefe; Ibrahim Akin

doi:10.3390/jcm9020486

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 Feb 10;9(2):486. doi: 10.3390/jcm9020486.

Authors

Fanis Buljubasic^{1

2}, Ibrahim El-Battrawy^{1

2}, Huan Lan³, Santosh K Lomada⁴, Anupriya Chatterjee⁴, Zhihan Zhao^{1

2}, Xin Li¹, Rujia Zhong¹, Qiang Xu¹, Mengying Huang¹, Zhenxing Liao¹, Siegfried Lang^{1

2}, Lukas Cyganek^{2

5}, Xiaobo Zhou^{1

2

3}, Thomas Wieland^{2

4}, Martin Borggrefe^{1

2}, Ibrahim Akin^{1

2}

Affiliations

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 (I_SK4), 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.

Keywords: SK4 channel; arrhythmia; arrhythmogenic right ventricular cardiomyopathy; human-induced pluripotent stem cell-derived cardiomyocyte; nucleoside diphosphate kinase.

Grants and funding

81Z0500204/Deutsches Zentrum für Herz-Kreislaufforschung