Differential control of cardiac pacemaker activity by PDE4 subfamily members

Authors:
Publisher website
Google Scholar
Abstract
Aims: The cAMP-specific phosphodiesterases 4B and 4D (PDE4B and PDE4D) are critical regulators of cardiac excitation-contraction coupling, but their role in controlling heart rate (HR) remains poorly defined. This study aimed to evaluate their respective contributions to cardiac automaticity. Methods and results: PDE4 activity, measured by a radioenzymatic assay, accounted for ∼60% of the total cAMP-hydrolytic activity in the mouse sinoatrial node (SAN). Western blot and in situ RNA fluorescence hybridization (RNAscopeTM) showed that both PDE4B and PDE4D are expressed in the SAN and in isolated pacemaker cardiomyocytes. HR, measured by electrocardiogram (ECG) telemetry, was increased in Pde4b knockout (Pde4b−/−) and Pde4d knockout (Pde4d−/−) mice compared with wild-type (WT) littermates, during both day and night. Upon autonomic nervous system blockade, elevated HR persisted in Pde4b−/− but not in Pde4d−/− mice. Consistently, isolated perfused hearts from Pde4b−/− mice beat faster than WT littermates, whereas Pde4d−/− did not. Increased automaticity in Pde4b−/− hearts was not accompanied by modified Ca2+ homeostasis in Fluo-4-loaded isolated SAN tissue, either at baseline or during β-adrenergic (β-AR) stimulation with 10 nM isoprenaline (ISO). In contrast, Pde4d−/− SAN challenged with ISO exhibited an increased total sarcoplasmic reticulum Ca2+ leak and prolonged Ca2+ transients. Patch-clamp recordings revealed an increased action potential firing rate in Pde4b−/− but not in Pde4d−/− pacemaker cardiomyocytes. In Pde4b−/− cells, basal and ISO-stimulated L-type calcium current (ICa,L) densities were not significantly altered, whereas funny current (If) density was increased. Conversely, Pde4d ablation did not alter basal ICa,L nor If. Conclusion: These results show that PDE4B controls intrinsic SAN automaticity by regulating the voltage clock through the pacemaker current If, whereas PDE4D regulates the calcium clock via β-AR-induced calcium release through RyR2.
Funding Information
  • Agence Nationale de la Recherche (ANR-16-CE14-0014)
  • Agence Nationale de la Recherche (ANR-19-CE14-0038-02)
  • Agence Nationale de la Recherche (ANR-21-CE14-0082-01)
  • Agence Nationale de la Recherche (ANR-23-CE14-0009)
  • Fédération Française de Cardiologie
  • Fondation Lefoulon Delalande
  • CORDDIM
  • Norges Idrettshøgskole (2R01HL055438-22)
  • Fondation pour la Recherche Médicale (#FDT202204015124)
  • Fondation Leducq (TNE 19CV03)

This publication has 62 references indexed in Scilit: