Life Sciences Université Paris-Saclay

Impairment of physiological functions of the endoplasmic reticulum (ER) induces the so-called ER stress. ER stress has been implicated in many cardiovascular diseases including ischemic heart, hypertrophy and heart failure. To overcome the deleterious effect of ER stress, an evolutionarily conserved adaptive response, known as Unfolded Protein Response (UPR), is activated in order to restore ER homeostasis and promote cell survival. However, in the case of prolonged or severe ER stress, apoptotic cell death is ultimately activated to eliminate stressed cells, thus contributing to the development of the pathology. The modulation of ER stress response, in order to reduce cardiomyocyte apoptosis, thus appears as a promising therapeutic strategy for such pathologies.

In an article that just appeared in Cell Death & Differentiation, Christophe Lemaire and his colleagues in the Faculty of Pharmacy of Châtenay-Malabry (Inserm-UPSud UMR-S 1180) studied the modification that occurs during ER stress response in the heart and the role of the sirtuin-1 (SIRT1) in the modulation of this response. SIRT1 is a deacetylase activated in response to many cardiac stresses to promote cell survival. Using isolated cardiomyocytes and SIRT1-KO mice, they demonstrated in vitro and in vivo (i) that SIRT1 is activated and plays a cardioprotective role in ER stress response, (ii) that SIRT1 attenuates the UPR by specifically regulating the PERK pathway, and (iii) that SIRT1 reduces PERK axis activation and apoptosis by deacetylating eIF2a on lysine residues K141 and K143.

Their results provide the first evidence that SIRT1 modulates ER stress-induced apoptosis in the heart and suggest that this deacetylase may represent a therapeutic target to prevent apoptosis in cardiac pathologies associated to ER stress.

Contact : christophe.lemaire@u-psud.fr

Projet sélectionné dans le cadre de l'appel à projets transnational pour la recherche sur les maladies cardiovasculaires (ERA-NET Cofund ERA-CVD)

Coordinator: Rodolphe Fischmeister, INSERM, Univ Paris-Sud, Université Paris-Saclay

In heart failure (HF) patients, the heart is unable to meet the hemodynamic needs, such as during a physical exercise or an emotional stress. The sympathetic nervous system, activated upon exercise or stress acts on the heart by the release of noradrenaline which activates beta-adrenergic receptors. Once activated, these receptors cause the production of cyclic AMP (cAMP). However, when the body demand stops, the heart returns to its normal activity by a family of enzymes called phosphodiesterases (PDEs). Thus, beta-adrenergic receptors serve as an accelerator and PDEs as a brake. In HF, the accelerator pedal is stuck to the floor and the brakes are ineffective. This project will use a new gene therapy approach to reintroduce different defective/missing types of PDEs into the heart, with the hope to prevent the associated heart rhythm disorders which are the main cause of death in HF.

Joël Doré a reçu la médaille d’Excellence Dupont Nutrition et Santé pour ses recherches sur le microbiote intestinal et son rôle dans certaines pathologies chroniques.