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

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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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Acknowledgements

We are grateful to David Bergerat (INSERM U1151-CNRS UMR8253) and Florence Lefebvre (Inserm UMR-S 1180, Faculté de Pharmacie Université Paris-Saclay) for their skillful help in preparing cell cultures.

Funding

This work was supported by grants from the French agency Agence Nationale de la Recherche (CERF ANR-13-BSV1-0002-01, EFIKAC ANR-16-CE14-0010) and Laboratory of Excellence GR-Ex (ANR-11-LABX-0051, ANR-11-IDEX-0005-02) and LERMIT (ANR-10-LABX-33, ANR-11-IDEX-0003-01).

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Authors and Affiliations

  1. INSERM U1151-CNRS UMR8253, Paris, France

    Marta Lindner, Hind Mehel, Amandine David, Christine Leroy, Martine Burtin, Gérard Friedlander, Fabiola Terzi & Dominique Prié

  2. Université de Paris Faculté de Médecine, Paris, France

    Gérard Friedlander & Dominique Prié

  3. Service de Physiologie Explorations Fonctionnelles Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

    Gérard Friedlander

  4. Université Paris-Saclay, Inserm U1180, 92296, Châtenay-Malabry, France

    Delphine Mika & Rodolphe Fischmeister

  5. Service de Physiologie Explorations Fonctionnelles Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France

    Dominique Prié

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  1. Marta Lindner
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Lindner, M., Mehel, H., David, A. et al. Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects. Basic Res Cardiol 115, 51 (2020). https://doi.org/10.1007/s00395-020-0810-6

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