ROLE OF TYPE 4 PHOSPHODIESTERASES IN CARDIAC PATHOPHYSIOLOGY – PDE4HEART

Cardiac hypertrophy is an adaptive mechanism that often leads to heart failure and sudden death. Heart failure is a major health problem representing about 2% of health costs in developed countries and this trend is predicted to increase. Chronic activation of the beta-adrenergic receptor (beta-AR)/cAMP cascade is centrally involved in cardiac hypertrophy and failure, as demonstrated by the beneficial effect of beta-blockers in this pathology. However, such medications are effective in only 40-50% of patients with heart failure, and they are ineffective in correcting deficits in exercise tolerance that contribute to a reduction in the quality of life. Therefore, it is imperative to better understand the signaling mechanisms acting downstream of beta-adrenergic receptors in order to propose novel therapeutics to treat heart failure. In the recent past, our team has crucially contributed to the understanding that physiological cAMP signaling is confined in specific subcellular domains and suggested that drawbacks of heart failure treatments are due to their bypass of compartmentalization. In particular, we identified type 4 phosphodiesterases (PDE4), which specifically hydrolyzes cAMP, as a major negative regulator of beta-AR signaling in cardiac myocytes. At the molecular level, PDE4 is extremely diverse with approximately 15 isoforms generated by three genes (PDE4A, PDE4B and PDE4D) in cardiac tissue. So far, the functional implication of this molecular diversity is unknown, except that ablation of the PDE4D gene in mice triggers a late onset dilated cardiomyopathy. The aim of this project is to provide new insight into the specific roles of PDE4 molecular variants in the control of cardiac excitation contraction coupling and pathological cardiac hypertrophy and heart failure. In particular, we will identify the role of PDE4B in the heart and test the hypothesis that PDE4 activation is beneficial in hypertrophy and HF. For this, the project will use genetically engineered mice models and a combination of physiological and molecular approaches at different levels of integration, ranging from in vivo exploration to single cell studies. The widely recognized expertise of our team in cyclic nucleotide signaling and cardiac physiology and the long lasting collaboration we established with Pr. Marco Conti (University of California at San Francisco), a world leader in the PDE4 field, provides the means to decipher the roles of PDE4 in cardiac pathophysiology and create value in the field of hypertrophy/HF.