PDE4HEART

Regardless of the underlying cause for heart failure (HF), patients show a neurohormonal overactivation in response to a decline in systolic function. This creates a pathophysiological “vicious circle” where chronic activation of ß-adrenergic signalling plays a central role as attested by the beneficial effect of ß-blockers in HF. In contrast, nitric oxide (NO) and natriuretic peptides (NPs) exert favourable effects in HF. The ß-adrenergic pathway results in an increase in cAMP levels to augment cardiac function, whereas NO and NPs signal through cGMP to exert opposite effects. Cyclic nucleotide (CN) levels are tightly regulated by their hydrolysis by phosphodiesterases (PDEs). The PDE superfamily comprises several distinct isoforms that regulate cAMP and cGMP in discrete microdomains of the cardiomyocyte and ensure the specificity of CN signalling in physiological conditions. However, this organization is lost in HF, thus causing further deterioration of the heart. While chronic PDE inhibition failed to show significant beneficial effects in HF treatment, our preliminary results indicate that it is PDE overexpression that has more promising effects. In this proposal, we intend to further validate this hypothesis and assess whether overexpression of specific PDEs in cardiomyocytes can prevent/reverse HF. To do so, the consortium will test whether gene therapy with cardiac targeted overexpression of three different PDE isoforms can restore CN compartmentation, prevent maladaptive cardiac remodelling and constitute a new therapeutic approach for HF.