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 F luo‐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 C a 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 C a 2+ ‐ ATP ase protein. Moreover, the FGF receptor inhibitor ( PD 173074, 10 nM), calmodulin inhibitor ( W 7, 5 μM) and phospholipase C inhibitor ( U 73122, 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.