Projet de thèse en Physiologie, physiopathologie
Sous la direction de Rodolphe Fischmeister.
Thèses en préparation à Paris Saclay , dans le cadre de Innovation thérapeutique du fondamental à l'appliqué , en partenariat avec Signalisation et physiopathologie cardiaque (laboratoire) et de Université Paris-Sud (établissement opérateur d'inscription) depuis le 01-01-2013 .
Pas de résumé en français disponible.
Cardiac targeted overexpression of PDE4B1 and PDE2A3 using Adeno-Associated Virus.
Heart failure (HF) is a major cause of morbidity and mortality in the Western world. While the majority of patients dies of worsening heart function, a significant proportion (30-50%) dies suddenly of cardiac arrhythmias.The β-adrenergic pathway results in an increase in cAMP which plays a key role in the regulation of cardiac automaticity, contractility and relaxation. While acute activation of β-adrenergic receptors (β-AR) improves cardiac function, their chronic stimulation by increased circulating catecholamines in HF leads to electrophysiological alterations and deregulation of intracellular calcium handling, and thus participates to the progression of the disease. Cyclic AMP levels are tightly regulated by phosphodiesterases (PDEs), the enzymes that degrade this second messenger. Since long term treatment with PDE inhibitors increases the mortality of HF patients we hypothesize that chronic β-AR activation in HF and persistent elevation of intracellular cAMP levels contribute to the progression of the disease and the associated arrhythmias as attested by the beneficial effect of β-blockers in HF. PDEs not only degrade this cAMP to terminate b-AR signals but also confine it within specific intracellular compartments to maintain specificity of the β-AR response. Recently, it has been shown that PDE2 expression is 2-fold higher in human and experimental HF. Increased PDE2 activity taking place in HF seems to blunt the cAMP-mediated toxic effects of excessive β-AR stimulation and hence, may constitute a defense mechanism during cardiac stress by antagonizing the effects of excessive catecholamines in HF. Unlike PDE2, PDE4 expression is decreased in pathological cardiac hypertrophy, which may cause a loss of cAMP compartmentation. Ablation of PDE4B gene in mice enhances the occurrence of ventricular tachycardia in response to β-AR stimulation. Thus, normal expression of PDE4B seems essential to regulate the excitation-contraction coupling in the heart to limit cardiac arrhythmias. Increasing myocardial expression of PDEs in HF may represent a new anti-adrenergic therapeutic strategy to treat HF. In a clinically relevant experimental setting we will focus on cardiac remodeling, left ventricular function, survival and lethal arrhythmias and characterize the beneficial effects of increased PDE2A and PDE4B at the cellular level.