title: 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.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Cardiology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan.
authors.forename: Shih-Yu
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsiung
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Chih
authors.initials: CC
authors.lastname: Chung
authors.affiliation: Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-I
authors.initials: TI
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Tzu-Chi General Hospital, Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Veterans General Hospital-Taipei, Taipei, Taiwan.
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011667:Pulmonary Veins / Q000166:cytology; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D053119:Benzophenanthridines; D001596:Benzylamines; D002118:Calcium; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D047428:Protein Kinase Inhibitors; D012964:Sodium; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C016299:chelerythrine
keywords: Pathology Section; atrial fibrillation; calcium regulation; fibroblast growth factor-23; late sodium current; pulmonary vein