ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes

Yu Hsun Kao, Jung Chieh Hsu, Yao Chang Chen, Yung Kuo Lin, Baigalmaa Lkhagva, Shih Ann Chen, Yi Jen Chen

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13 Citations (Scopus)

Abstract

Background ZFHX3 plays an important role in the genesis of atrial fibrillation. However, the atrial electrophysiological effects of ZFHX3 are not clear. This study sought to investigate roles of ZFHX3 in atrial electrophysiology and calcium homeostasis by using HL-1 atrial myocytes knocked-down with ZFHX3. Methods Patch clamp, confocal fluorescence microscopy and Western blot were used to study electrical activity, ionic currents, calcium homeostasis and protein expressions in stable ZFHX3 shRNA cells. Results As compared to control, ZFHX3 shRNA cells with 28% decline of ZFHX3 protein had a larger sarcoplasmic reticulum Ca2+ content by 62%, Ca2+ transient by 20%, and calcium leak by 75%. ZFHX3 shRNA cells (n = 35) had shorter action potential duration (APD) at 50% (14.7 ± 0.9 versus 20.3 ± 1.4 ms, P <0.005), and 20% (6.1 ± 0.3 versus 8.3 ± 0.8 ms, P <0.005) repolarization than control cells (n = 30). ZFHX3 shRNA cells (n = 10) had larger amplitudes of isoproterenol (1 μM)-induced delayed afterdepolarization (14.1 ± 0.9 versus 7.2 ± 0.2 mV, P <0.05) than control cells (n = 10). Besides, acetylcholine (3 μM) shortened APD at 90% repolarization to a greater extent (19 ± 4% versus 7 ± 2%, P <0.01) in ZFHX3 shRNA cells (n = 11) than in control cells (n = 12). In addition, ZFHX3 shRNA cells had increased expressions of SERCA2a, ryanodine receptor, Kv1.4, Kv1.5 and Kir3.4. Moreover, ZFHX3 shRNA cells had a larger SERCA2a activity, ultra-rapid delayed rectifier potassium currents, transient outward currents and acetylcholine-sensitive potassium currents. Conclusions ZFHX3 knock-down in atrial myocytes dysregulated calcium homeostasis and increased atrial arrhythmogenesis, which may contribute to the occurrence of AF.

Original languageEnglish
Pages (from-to)85-92
Number of pages8
JournalInternational Journal of Cardiology
Volume210
DOIs
Publication statusPublished - May 1 2016

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Keywords

  • Atrial arrhythmogenesis
  • Calcium homeostasis
  • ZFHX3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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