Cardiac-Specific Overexpression of Phosphodiesterase 2 (PDE2) in Mouse is Cardioprotective

Phosphodiesterase 2 (PDE2) is a dual substrate enzyme, hydrolyzing both cAMP and cGMP. We showed that myocardial PDE2 is upregulated in human and experimental heart failure (HF) while PDE3 and PDE4 are reduced. To explore the pathophysiological consequences of enhanced PDE2 activity, transgenic mice with a heart-specific overexpression of the PDE2A3 isoform (PDE2-TG) were generated.PDE2 activity was measuredin heart extractsby radioenzymatic assay. Sarcomere shortening, Ca2+ transients and L-type Ca2+ current (ICa,L) were recorded in adult ventricular cardiomyocytes from wild-type (WT) and PDE2-TG mice. SR Ca2+ leak was estimated with tetracaine (RyR blocker) and spontaneous Ca2+ waves (SCW) were recorded during 30s pacing pause. Intracellular cAMP level was measured with FRET. Phosphorylation level of excitation-contraction coupling (ECC) proteins was determined by Western Blot. Heart function was investigated by echocardiography and ECG-telemetry. Isoprenaline (ISO) was used to compare β-adrenergic (β-AR) response of all parameters in WT and PDE2-TG mice.cAMP and cGMP-PDE2 activity was strongly increased in PDE2-TG as compared to WT mice. Resting and maximal heart rate was markedly reduced in PDE2-TG mice. The β-AR stimulation of cell contractility, Ca2+ transient, ICa,L and [cAMP]i was severely blunted. PDE2-TG mice showed reduced SR Ca2+ leak and SCW (both at the cellular and in vivo levels), without changes in Ca2+ load as compared to WT during β-AR activation. PDE2-TG mice showed a lower basal phosphorylation of ECC proteins and have a longer lifespan than their WT littermates. All effects of PDE2 overexpression were reversed by PDE2 inhibitor, Bay-607550.Our results demonstrate that PDE2 plays a critical role in the regulation of cardiac ECC. PDE2 overexpression appears to protect the cardiomyocytes by reducing Ca2+-leakage and arrhythmias during β-AR stimulation. PDE2 may represent a new therapeutic strategy in heart failure.