The impact of phosphodi­esterase 2 on heart function and development of arrhythmia – a target for antiarrhythmic therapy?

Ventricular arrhythmia and sudden cardiac death represent main causes for mortality in patients suffering from diabetic cardiomyopathy as well as from acute myocardial infarction. Anti-arrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Novel concepts aim at activating protective pathways, such as additional augmentation of the natriuretic peptide (NP) system. The C-type natriuretic peptide (CNP) was shown to promote beneficial anti-hypertrophic and vasodilatory effects. Phosphodiesterases (PDEs) are hydrolysing enzymes that degrade the second messengers cAMP and cGMP. In contrast to other cardiac PDEs, PDE2 is upregulated in human heart failure (HF) and in models of experimental diabetic cardiomyopathy. A key mechanism involved in HF is the permanent stimulation of β-adrenoreceptors (β-AR) mediating high levels of cAMP and chronic activation of downstream-targets such as ryanodine receptors (RyR2). Interestingly, PDE2 has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP thus mediating a negative cross-talk between cAMP- and cGMP signaling pathways.

Here, we aim to investigate the impact of PDE2 on calcium handling and heart function establishing and using the new cardiac specific PDE2 knockout (KO) mouse model. We aim to elucidate potential anti-arrhythmic effects of cGMP-mediated PDE2 stimulation using CNP. Our results show that genetic deletion of PDE2 in cardiomyocytes (PDE2 KO) did not affect heart function including heart rate and contractility at basal conditions and after β-adrenergic stimulation. At cellular level, PDE2 KO did not influence intracellular Ca²⁺ cycling and cellular contractility displaying similar Ca²⁺ transient amplitudes and numbers of spontaneous Ca²⁺ releases via RyR2, called Ca²⁺ sparks (CaSp), in KO and WT. However, after β-AR stimulation with the agonist isoprenaline (ISO), Ca²⁺ transient amplitudes as well as the number of spontaneous arrhythmogenic Ca²⁺ waves (SCW) were significantly higher in KO compared to WT. The results indicate that the cardiac PDE2 deletion might promote the development of cardiac arrhythmia. To test a possible anti-arrhythmic function of CNP-induced PDE2 stimulation, we detected the number of arrhythmogenic SCW and CaSp upon β-AR stimulation with ISO in isolated murine cardiomyocytes from WT and PDE2 KO mice. Interestingly, CNP significantly reduced the ISO-mediated increase in CaSp and SCW. The CNP effect was either blunted by pharmacological PDE2 inhibition or prevented by cardiac-specific PDE2 KO. Additionally, CNP significantly lowered CaSp frequency in human iPS-derived cardiomyocytes that was not observed upon PDE2 inhibition.

We conclude that PDE2 stimulation by CNP protected against cardiac arrhythmia in isolated cardiomyocytes reducing intracellular Ca²⁺ dependent trigger mechanisms. Consequently, increasing PDE2 activity may represent a novel anti-arrhythmic therapeutic strategy.

Publications:

Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation.  S.R. Kunzel, M.0. Hoffmann, S. Weber, K. Kunzel, S. Kammerer, M. Gunscht, E. Klapproth, J.S.E. Rausch, M.S. Sadek, T. Kolanowski, S. Meyer-Roxlau, C. Piorkowski, S.M. Tugtekin, S. Rose-John, X. Yin, M. Mayr, J.D. Kuhlmann, P. Wimberger, K. Grutzmann, N. Herzog, J.H. Kupper, M. O'Reilly, S.N. Kabir, L.C. Sommerfeld, K. Guan, B. Wielockx, L. Fabritz, S. Nattel, U. Ravens, D. Dobrev, M. Wagner, A. El-Armouche. Circ Res 2021; 129(8):804-820.