Oncotarget

Research Papers: Pathology:

Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes

Shih-Yu Huang, Yao-Chang Chen, Yu-Hsun Kao, Ming-Hsiung Hsieh, Yung-Kuo Lin, Cheng-Chih Chung, Ting-I Lee, Wen-Chin Tsai, Shih-Ann Chen and Yi-Jen Chen _

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Oncotarget. 2016; 7:69231-69242. https://doi.org/10.18632/oncotarget.12470

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Abstract

Shih-Yu Huang1,2, Yao-Chang Chen3, Yu-Hsun Kao1,4, Ming-Hsiung Hsieh5,6, Yung-Kuo Lin5,6, Cheng-Chih Chung1,5, Ting-I Lee7,8, Wen-Chin Tsai9, Shih-Ann Chen10 and Yi-Jen Chen1,5

1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

2 Division of Cardiology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan

3 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan

4 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

5 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

6 Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

7 Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 

8 Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 

9 Division of Cardiology, Tzu-Chi General Hospital, Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan 

10 Division of Cardiology and Cardiovascular Research Center, Veterans General Hospital-Taipei, Taipei, Taiwan

Correspondence to:

Yi-Jen Chen, email:

Keywords: atrial fibrillation, calcium regulation, fibroblast growth factor-23, pulmonary vein, late sodium current, Pathology Section

Received: July 25, 2016 Accepted: September 29, 2016 Published: October 04, 2016

Abstract

Fibroblast growth factor 23 (FGF23), elevated in chronic renal failure, increases atrial arrhythmogenesis and dysregulates calcium homeostasis. Late sodium currents (INa-Late) critically induces ectopic activity of pulmoanry vein (the most important atrial fibrillation trigger). This study was to investigate whether FGF23 activates the INa-Late leading to calcium dysregulation and increases PV arrhythmogenesis. Patch clamp, western blot, and confocal microscopy were used to evaluate the electrical activities, calcium homeostasis, and mitochondrial reactive oxygen species (ROS) in PV cardiomyocytes with or without FGF23 (0.1 or 1 ng/mL) incubation for 4~6 h. Compared to the control, FGF23 (1 ng/mL, but not 0.1 ng/mL)-treated PV cardiomyocytes had a faster beating rate. FGF23 (1 ng/mL)-treated PV cardiomyocytes had larger INa-Late, calcium transients, and mitochondrial ROS than controls. However, ranolazine (an inhibitor of INa-Late) attenuated FGF23 (1 ng/mL)-increased beating rates, calcium transients and mitochondrial ROS. FGF23 (1 ng/mL)-treated PV cardiomyocytes exhibited larger phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). Chelerythrine chloride (an inhibitor of protein kinase C) decreased INa-Late in FGF23 (1 ng/mL)-treated PV cardiomyocytes. However, KN93 (a selective CaMKII blocker) decreased INa-Late in control and FGF23 (1 ng/mL)-treated PV cardiomyocytes to a similar extent. In conclusion, FGF23 increased PV arrhythmogenesis through sodium and calcium dysregulation by acting protein kinase C signaling.


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