Impact of PDE2 modulation in Heart Failure and Arrhythmia

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Heart failure and lethal ventricular arrhythmias remain one of the leading causes of mortality worldwide and innovative therapeutic concepts are highly desired. While traditional therapies inhibit the deleterious activation of neurohormonal systems (such as the β-adrenergic pathway and the renin-angiotensin-aldosterone system), novel concepts also aim at activating protective pathways, e.g. additional augmentation of the natriuretic peptide (NP) system. Phosphodiesterase 2 (PDE2) is a signalling node, connecting the β-adrenergic and NP systems. Among the PDEs, it has the unique property to be stimulated by cGMP leading to increased cAMP hydrolysis and thus mediating a negative cross-talk between cAMP/cGMP pathways. While the pathophysiological role of PDE2 in the heart is in a large part unknown and still being controversially discussed, our data point to a cardioprotective and antiarrhythmic role of PDE2 as well as of PDE2-mediated cGMP/cAMP crosstalk in heart disease. Our goal is to define the physiological and pathophysiological role of PDE2 in the heart. To this aim, we will capitalize from newly developed cardiac-specific PDE2 knockout models. We will combine in vivo and in vitro techniques to decipher the impact of PDE2 on cardiac function as well as its functions in subcellular cGMP/cAMP crosstalk. We will validate our main findings in an inducible cardiac-specific PDE2 knockout model. Moreover, we will provide mechanistic insights into cardiac subcellular cAMP-regulation by the three PDE2 isoforms under physiological conditions, into the antiarrhythmic effects of PDE2 at animal, organ and cellular level and into PDE2 functions during cardiac remodeling in established heart failure models. Finally, we will provide proof-of-concept of therapeutic PDE2 stimulation by pharmacological treatment of wild type and PDE2 KO mice with cGMP-enhancing NO-donors as well as NPs. Unravelling the mechanistic role of PDE2 in heart failure and arrhythmias may serve to develop innovative new therapeutic approaches by pharmacologically modulating PDE2 activity.