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

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.

DOI: 10.18632/oncotarget.12470

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Cite this paper

@inproceedings{Huang2016FibroblastGF, title={Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes}, author={Shih-Yu Huang and Yao-Chang Chen and Yu-Hsun Kao and Ming-Hsiung Hsieh and Yung-Kuo Lin and Cheng-Chih Chung and Ting-I Lee and W. C. Tsai and Shih-ann Chen and Yi-Jen Chen}, booktitle={Oncotarget}, year={2016} }