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Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes
|Authors:||Navarro-García, Jose A.; Delgado, Carmen ; Fernández-Velasco, María ; Val-Blasco, Almudena; Rodríguez-Sánchez, Elena; Aceves‑Ripoll, Jennifer; Gómez-Hurtado, Nieves; Bada-Bosch, Teresa; Mérida-Herrero, Evangelina; Hernández, Eduardo; Praga, Manuel; Salguero, Rafael; Solís, Jorge; Arribas, Fernando; Delgado, Juan F.; Bueno, Héctor; Kuro-o, Makoto; Ruilope, Luis M.; Ruiz-Hurtado, Gema|
|Publisher:||Oxford University Press|
|Citation:||Nephrology Dialysis Transplantation 34(11): 864–1875 (2019)|
|Abstract:||[Background]: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation–contraction (EC) coupling.|
[Methods]: We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram.
[Results]: Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho).
[Conclusions]: Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD.
|Publisher version (URL):||https://doi.org/10.1093/ndt/gfy392|
|Appears in Collections:||(IIBM) Artículos|