FGF-23 dysregulates calcium homeostasis and electrophysiological properties in HL-1 atrial cells

Eur J Clin Invest. 2014 Aug;44(8):795-801. doi: 10.1111/eci.12296.

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.

Keywords: Atrial arrhythmogenesis; calcium-handling protein; calcium/calmodulin-dependent protein kinase II; fibroblast growth factor-23.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Arrhythmias, Cardiac / physiopathology
  • Calcium / metabolism*
  • Calcium-Binding Proteins / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Estrenes / pharmacology
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / pharmacology
  • Fibroblast Growth Factors / physiology*
  • Heart Atria / metabolism
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • Humans
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Pyrrolidinones / pharmacology
  • Sodium-Calcium Exchanger / drug effects
  • Sulfonamides / pharmacology

Substances

  • Calcium-Binding Proteins
  • Estrenes
  • FGF23 protein, human
  • PD 173074
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrrolidinones
  • Sodium-Calcium Exchanger
  • Sulfonamides
  • phospholamban
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Fibroblast Growth Factors
  • W 7
  • Fibroblast Growth Factor-23
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium