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Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression

Michael Wagner1,2, Mirna S Sadek1, Nataliya Dybkova3,4

  • 1Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany.

International Journal of Molecular Sciences
|June 2, 2021
PubMed
Abstract

Insights

Phosphodiesterase 2 (PDE2) overexpression protects against cardiac arrhythmia by preventing abnormal ion channel activity. This suggests that activating PDE2 could be a new therapeutic approach for heart failure patients prone to arrhythmias.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Pharmacology

Background:

  • Phosphodiesterases (PDEs) regulate cyclic nucleotide levels in the heart.
  • PDE2, stimulated by cGMP, hydrolyzes cAMP, creating a negative crosstalk between signaling pathways.
  • PDE2 upregulation in heart failure contributes to desensitization to beta-adrenergic stimulation and increases arrhythmia susceptibility.

Purpose of the Study:

  • To investigate the mechanisms by which PDE2 overexpression protects against cardiac arrhythmias.
  • To determine the role of PDE2 in regulating ion currents and calcium handling during adrenergic stimulation.

Main Methods:

  • Assessment of cellular arrhythmias, ion currents (ICaL, INaL), and Ca2+-sparks in ventricular cardiomyocytes from PDE2 overexpressing (OE) and wild-type (WT) mice.
  • Stimulation with isoprenaline (ISO) to mimic beta-adrenergic overstimulation.
  • Evaluation of PDE2 inhibition in ex vivo perfused WT hearts subjected to reperfusion injury.

Main Results:

  • Isoprenaline (ISO) induced afterdepolarizations and spontaneous action potentials in WT, which were significantly reduced in PDE2 OE mice.
  • ISO-induced increases in ICaL and Epac/CaMKII-dependent increases in INaL and Ca2+-spark frequency were blunted in PDE2 OE.
  • PDE2 inhibition exacerbated arrhythmic events in reperfused WT hearts.

Conclusions:

  • Increased PDE2 abundance confers protection against ISO-induced cardiac arrhythmia.
  • This protection is mediated by preventing Epac- and CaMKII-dependent increases in cellular arrhythmogenic triggers.
  • Myocardial PDE2 activation presents a potential novel anti-arrhythmic therapeutic strategy for heart failure.
Keywords:
CaMKIIPDE2arrhythmiaheart failure

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