Abstract 17175: Phoshodiesterase 2 - A New Member Of Proteins Involved In Beta-adrenergic Desensitization
Diminished cAMP- and augmented cGMP-signaling is characteristic for failing hearts. Among the PDE superfamily, phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, but primarily hydrolysis cAMP. This appears to mediate a negative cross-talk between cAMP- and cGMP signaling pathways. However, the role of PDE2 in the heart is only poorly understood. Here, we investigated whether myocardial PDE2 is altered in heart failure (HF) and determined PDE2 mediated effects in isolated cardiomyocytes, in a cardiac stress model as well as in PDE2 heart-specific transgenic mice (TGs).
Immunoblotting revealed that myocardial left-ventricular PDE2 expression was ~2-fold higher in patients with end-stage heart failure. Accordingly, chronic beta-AR stimulation via isoprenaline infusions in rats induced a similar increase in PDE2 expression accompanied by an enhanced PDE2 cAMP hydrolytic activity of 4-fold compared to NaCl-controls. Cardiomyocytes isolated from this model showed blunted cardiac beta-AR responsiveness as determined by FRET-based sensors and ionoptix measurements, respectively. Importantly, this expected beta-AR desensitization was partly reversible upon application of the PDE2 specific inhibitor BAY 60-7550. Moreover, in vivo i.p. injections of BAY 60-7550 normalized dysfunctional beta-AR inotropic responsiveness in ISO hearts but interestingly also induced significant positive chronotropic responses in both ISO- and NaCl-hearts on top of maximal beta-AR stimulation with dobutamine. Conversely, ECG telemetry in PDE2-TGs showed a marked reduction in resting heart rate. Echocardiographic analysis of aging the PDE2-TG (15 month) showed preserved cardiac output at rest with no indication of any morphological cardiac pathology.
PDE2 maintains resting heart rate in the healthy heart but becomes markedly upregulated in the diseased ventricles and desensitizes against beta-AR mediated chronotropic and inotropic effects. This may constitute an important defence mechanism during cardiac stress with excessive adrenergic drive. Thus, activating myocardial PDE2 may represent a novel intracellular anti-adrenergic and heart rate maintaining therapeutic strategy in HF.
- © 2013 by American Heart Association, Inc.