Grégoire Vandecasteele PhD Cardiac Physiology
Course and current status
Current position : CR1 INSERM RESEARCHER at INSERM UMR-S 769
(Director R Fischmeister)
University Paris-Sud 11, Faculty of Pharmacy, Châtenay-Malabry, France.
Previous positions:
2002-06: CR2 INSERM, UMR-S 769, University Paris-Sud 11 Faculté de Pharmacie, Châtenay-Malabry (Director: Rodolphe Fischmeister)
2000-01: Post-doctoral fellow, Laboratory of Calcium Signalling, University of Ferrara, Ferrara, Italy. (Director: Rosario Rizzuto)
Scientific summary
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. Our current research aims at understanding the role of the different PDE4 isoforms in the regulation of cardiac excitation-contraction coupling, hypertrophy. and arrythmias.
