title: FGF-23 dysregulates calcium homeostasis and electrophysiological properties in HL-1 atrial cells.
abstract: BACKGROUND
  Fibroblast growth factor (FGF)-23 is a key regulator of phosphate homeostasis. Higher FGF-23 levels are correlated with poor outcomes in cardiovascular diseases. FGF-23 can produce cardiac hypertrophy and increase intracellular calcium, which can change cardiac electrical activity. However, it is not clear whether FGF-23 possesses arrhythmogenic potential through calcium dysregulation. Therefore, the purposes of this study were to evaluate the electrophysiological effects of FGF-23 and identify the underlying mechanisms.
  
  
  METHODS
  Patch clamp, confocal microscope with Fluo-4 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, calcium homeostasis and calcium regulatory proteins in HL-1 atrial myocytes with and without FGF-23 (10 and 25 ng/mL) incubation for 24 h.
  
  
  RESULTS
  FGF-23 (25 ng/mL) increased L-type calcium currents, calcium transient and sarcoplasmic reticulum Ca(2+) contents in HL-1 cells. FGF-23 (25 ng/mL)-treated cells (n = 14) had greater incidences (57%, 17% and 15%, P < 0·05) of delayed afterdepolarizations than control (n = 12) and FGF-23 (10 ng/mL)-treated cells (n = 13). Compared with control cells, FGF-23 (25 ng/mL)-treated cells (n = 14) exhibited increased phosphorylation of calcium/calmodulin-dependent protein kinase IIδ and phospholamban (PLB) at threonine 17 but had similar phosphorylation extents of PLB at serine 16, total PLB and sarcoplasmic reticulum Ca(2+) -ATPase protein. Moreover, the FGF receptor inhibitor (PD173074, 10 nM), calmodulin inhibitor (W7, 5 μM) and phospholipase C inhibitor (U73122, 1 μM) attenuated the effects of FGF-23 on calcium/calmodulin-dependent protein kinase II phosphorylation.
  
  
  CONCLUSIONS
  FGF-23 increases HL-1 cells arrhythmogenesis with calcium dysregulation through modulating calcium-handling proteins.
authors.affiliation: Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.forename: Rong-Jie
authors.initials: RJ
authors.lastname: Shiu
authors.forename: Tze-Fan
authors.initials: TF
authors.lastname: Chao
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology / Q000502:physiology*; D006325:Heart Atria / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004963:Estrenes; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011760:Pyrrolidinones; D019831:Sodium-Calcium Exchanger; D013449:Sulfonamides; D000099211:Phospholamban; C000717427:FGF23 protein, human; C115711:PD 173074; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C017967:W 7
keywords: Atrial arrhythmogenesis; calcium-handling protein; calcium/calmodulin-dependent protein kinase II; fibroblast growth factor-23