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01.09.2020 | Original Contribution

Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects

verfasst von: Marta Lindner, Hind Mehel, Amandine David, Christine Leroy, Martine Burtin, Gérard Friedlander, Fabiola Terzi, Delphine Mika, Rodolphe Fischmeister, Dominique Prié

Erschienen in: Basic Research in Cardiology | Ausgabe 5/2020

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Abstract

The concentration of fibroblast growth factor 23 (FGF23) rises progressively in renal failure (RF). High FGF23 concentrations have been consistently associated with adverse cardiovascular outcomes or death, in chronic kidney disease (CKD), heart failure or liver cirrhosis. We identified the mechanisms whereby high concentrations of FGF23 can increase the risk of death of cardiovascular origin. We studied the effects of FGF23 and Klotho in adult rat ventricular cardiomyocytes (ARVMs) and on the heart of mice with CKD. We show that FGF23 increases the frequency of spontaneous calcium waves (SCWs), a marker of cardiomyocyte arrhythmogenicity, in ARVMs. FGF23 increased sarcoplasmic reticulum Ca²⁺ leakage, basal phosphorylation of Ca²⁺-cycling proteins including phospholamban and ryanodine receptor type 2. These effects are secondary to a decrease in phosphodiesterase 4B (PDE4B) in ARVMs and in heart of mice with RF. Soluble Klotho, a circulating form of the FGF23 receptor, prevents FGF23 effects on ARVMs by increasing PDE3A and PDE3B expression. Our results suggest that the combination of high FGF23 and low sKlotho concentrations decreases PDE activity in ARVMs, which favors the occurrence of ventricular arrhythmias and may participate in the high death rate observed in patients with CKD.

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Titel: Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects
verfasst von: Marta Lindner
Hind Mehel
Amandine David
Christine Leroy
Martine Burtin
Gérard Friedlander
Fabiola Terzi
Delphine Mika
Rodolphe Fischmeister
Dominique Prié
Publikationsdatum: 01.09.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 5/2020
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-020-0810-6

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