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Calmodulin kinase II inhibition limits the pro-arrhythmic Ca2+ waves induced by cAMP-phosphodiesterase inhibitors

Pierre Bobin1, Audrey Varin1, Florence Lefebvre1

  • 1Inserm, UMR-S 1180, Univ. Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France.

Cardiovascular Research
|February 7, 2016
PubMed
Abstract

Insights

Phosphodiesterase (PDE) inhibitors enhance heart contraction via PKA but can cause arrhythmias through PKA and CaMKII pathways. CaMKII inhibitors may mitigate these pro-arrhythmic effects in heart failure treatment.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Cardiac Electrophysiology

Background:

  • Phosphodiesterase (PDE) inhibitors are used in heart failure, but concerns exist regarding their pro-arrhythmic potential.
  • PDE inhibitors increase cyclic adenosine monophosphate (cAMP), enhancing protein kinase A (PKA) activity and cardiac contraction.
  • The role of Ca2+ signaling pathways, including CaMKII and Epac, in PDE inhibitor-induced arrhythmias remains unclear.

Purpose of the Study:

  • To investigate the involvement of PKA, CaMKII, and Epac pathways in the pro-arrhythmic effects of PDE inhibitors.
  • To determine the mechanisms underlying PDE inhibitor-induced spontaneous diastolic Ca2+ waves (SCWs) in ventricular myocytes.

Main Methods:

  • Isolated adult rat ventricular myocytes were used to measure intracellular Ca2+ and sarcomere shortening.
  • Electrophysiological recordings and biochemical assays were performed to assess Ca2+ cycling, SR Ca2+ load, and protein phosphorylation.
  • Specific inhibitors for PDE4, PDE3, PKA, CaMKII, Epac1, and Epac2 were employed.

Main Results:

  • PDE4 inhibition (Ro 20-1724) enhanced isoprenaline-induced inotropic effects and promoted spontaneous diastolic Ca2+ waves (SCWs).
  • PDE inhibition increased RyR2 and PLB phosphorylation at PKA and CaMKII sites, leading to increased SR Ca2+ load and leak.
  • CaMKII inhibition reduced SR Ca2+ leak and SCW incidence, while PKA inhibition blocked all effects of isoprenaline and PDE4 inhibition.

Conclusions:

  • PDE inhibitors exert inotropic effects through PKA activation.
  • PDE inhibitors induce SCWs via combined PKA and CaMKII activation, partly through Epac2.
  • CaMKII inhibitors may serve as adjuncts to PDE inhibitors to reduce their pro-arrhythmic risks in heart failure.
Keywords:
5′–3′ cyclic nucleotide phosphodiesterasesArrhythmiaCaMKIIcAMPβ-adrenergic receptors

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