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

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

doi:10.18632/oncotarget.12470

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.

Highlights

Atrial fibrillation (AF) is the most often seen cardiac arrhythmia to cause heart failure and cardiovascular events in clinical practice. [1, 2] A previous study reported that fibroblast growth factor 23 (FGF23), a regulatory hormone secreted by osteocytes for phosphate-calcium homeostasis, can increase the incidence of AF. [3,4,5] High circulating levels of FGF23 in chronic kidney disease (CKD) linked to an elevated prevalence of AF. [6,7,8,9] FGF23 was shown to induce atrial arrhythmogenesis due to calcium dysregulation with increased phosphorylation of calcium/ calmodulin-dependent protein kinase II (CaMKII). [1013] Pulmonary vein (PV) is the most important focus of initiating AF. [14,15,16] Our previous animal study showed that CKD PVs had increased arrhythmogenesis
[10] In the present study, we found that FGF23 at a concentration of 1 ng/ mL increased PV spontaneous activity and amplitude of delayed afterdepolarizations (DADs), which may have been caused by FGF23-increased NCX currents. [26, 27] In addition, the shorter action potential duration (APD) in FGF23 (1 ng/mL)-treated PV cardiomyocytes may be caused by their larger NCX currents and faster beating rates
The increase of INa-Late can induce calcium overload through calcium entry from the NCX in PV cardiomyocytes and lead to arrhythmogenesis. [2931] We found that FGF23 increased the INa-Late in PV cardiomyocytes, and ranolazine inhibited the effects of FGF23 on PV arrhythmogenesis

Summary

Introduction

Atrial fibrillation (AF) is the most often seen cardiac arrhythmia to cause heart failure and cardiovascular events in clinical practice. [1, 2] A previous study reported that fibroblast growth factor 23 (FGF23), a regulatory hormone secreted by osteocytes for phosphate-calcium homeostasis, can increase the incidence of AF. [3,4,5] High circulating levels of FGF23 in chronic kidney disease (CKD) linked to an elevated prevalence of AF. [6,7,8,9] FGF23 was shown to induce atrial arrhythmogenesis due to calcium dysregulation with increased phosphorylation of calcium/ calmodulin-dependent protein kinase II (CaMKII). [1013] Pulmonary vein (PV) is the most important focus of initiating AF. [14,15,16] Our previous animal study showed that CKD PVs had increased arrhythmogenesis. [17] FGF23 is hypothesized to induce the high incidence of AF in CKD patients through increasing PV electrical activity.FGF23 is known to produce cardiac hypertrophy by activating calcineurin with concomitant promotion of protein kinase C (PKC), which can increase late sodium current (INa-Late) in the cardiomyocyte. [11, 18,19,20,21,22] FGF23 increases cellular reactive oxygen species (ROS). [23] Mitochondria ROS are the mian source of cellular ROS in the cardiomyocyte. [24] Up-regulation of INa-Late can lead to overproduction of mitochondrial ROS and oxidation of CaMKII, resulting in abnormalities of calcium handling. [25] The purpose of this study was to investigate whether FGF23 increases PV arrhythmogenesis and the potential underlying mechanisms. [1, 2] A previous study reported that fibroblast growth factor 23 (FGF23), a regulatory hormone secreted by osteocytes for phosphate-calcium homeostasis, can increase the incidence of AF. [6,7,8,9] FGF23 was shown to induce atrial arrhythmogenesis due to calcium dysregulation with increased phosphorylation of calcium/ calmodulin-dependent protein kinase II (CaMKII). [14,15,16] Our previous animal study showed that CKD PVs had increased arrhythmogenesis. [17] FGF23 is hypothesized to induce the high incidence of AF in CKD patients through increasing PV electrical activity. FGF23 is known to produce cardiac hypertrophy by activating calcineurin with concomitant promotion of protein kinase C (PKC), which can increase late sodium current (INa-Late) in the cardiomyocyte.

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