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

Authors
  • Lindner, Marta1
  • Mehel, Hind1
  • David, Amandine1
  • Leroy, Christine1
  • Burtin, Martine1
  • Friedlander, Gérard1, 2, 3
  • Terzi, Fabiola1
  • Mika, Delphine4
  • Fischmeister, Rodolphe4
  • Prié, Dominique1, 2, 3
  • 1 INSERM U1151-CNRS UMR8253, Paris, France , Paris (France)
  • 2 Université de Paris Faculté de Médecine, Paris, France , Paris (France)
  • 3 Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 4 Université Paris-Saclay, Inserm U1180, Châtenay-Malabry, 92296, France , Châtenay-Malabry (France)
Type
Published Article
Journal
Basic Research in Cardiology
Publisher
Springer Berlin Heidelberg
Publication Date
Jul 22, 2020
Volume
115
Issue
5
Identifiers
DOI: 10.1007/s00395-020-0810-6
Source
Springer Nature
Keywords
License
Yellow

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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