Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Abstract

Background: The cAMP-hydrolyzing phosphodiesterase 4B (PDE4B) is a key negative regulator of cardiac β-adrenergic receptor (β-AR) stimulation. PDE4B deficiency leads to abnormal Ca²⁺ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure (HF). Methods: We measured PDE4B expression in human cardiac tissues, developed two transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B (PDE4B-TG), and an adeno-associated virus serotype 9 encoding PDE4B (AAV9-PDE4B). Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Cyclic AMP and PKA activity were monitored by Förster resonance energy transfer, I_Ca,L by whole cell patch-clamp, and cardiomyocyte shortening and Ca²⁺ transients with an Ionoptix^® system. HF was induced by 2 weeks infusion of isoproterenol (Iso) or transverse aortic constriction (TAC). Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-TG mouse line (TG15) had a ~15-fold increase in cardiac cAMP-PDE activity and a ~30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-AR stimulation of cardiac inotropy, cAMP, PKA, I_Ca,L, Ca²⁺ transients and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion and fibrosis induced by chronic Iso treatment. In the second PDE4B-TG mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ~50-fold increase in cardiac cAMP-PDE activity caused a ~50% decrease in fractional shortening, hypertrophy, dilatation and premature death. In contrast, mice injected with AAV9-PDE4B (10¹² viral particles/mouse) had a ~50% increase in cardiac cAMP-PDE activity which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis and fibrosis, while attenuating hypertrophy induced by chronic Iso infusion. Similarly, AAV9-PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion and prevented apoptosis and fibrotic remodeling in TAC. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat HF.