Malik Bisserier1, Magali Berthouze-Duquesnes1, Magali Breckler1, Florence Tortosa1, Loubina Fazal1, Annélie de Régibus1, Anne-Coline Laurent1, Audrey Varin1, Alexandre Lucas1, Maxime Branchereau1, Pauline Marck1, Jean-Nicolas Schickel1, Claudine Deloménie1, Olivier Cazorla1, Pauline Soulas-Sprauel1, Bertrand Crozatier1, Eric Morel1, Christophe Heymes1, Frank Lezoualc'h2. 1. From Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (M.B., M.B.-D., M.B., F.T., L.F., A.d.R., A.-C.L., A.L., M.B., P.M., C.H., F.L.); Université Toulouse III-Paul Sabatier, Toulouse, France (M.B., M.B.-D., M.B., F.T., L.F., A.d.R., A.-C.L., A.L., C.H., F.L.); Université Paris Sud, IFR141 IPSIT, Châtenay-Malabry, France (A.V., C.D., B.C., E.M.); Inserm, UMR-S769, Châtenay-Malabry, France (A.V., C.D., B.C., E.M.); CNRS UPR 3572, IBMC, Strasbourg, Faculty of Pharmacy, France, Strasbourg, France (J.-N.S., P.S.-S.); and Inserm, U1046, Université Montpellier 1, Université Montpellier 2, CHRU Montpellier, Montpellier, France (O.C.). 2. From Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (M.B., M.B.-D., M.B., F.T., L.F., A.d.R., A.-C.L., A.L., M.B., P.M., C.H., F.L.); Université Toulouse III-Paul Sabatier, Toulouse, France (M.B., M.B.-D., M.B., F.T., L.F., A.d.R., A.-C.L., A.L., C.H., F.L.); Université Paris Sud, IFR141 IPSIT, Châtenay-Malabry, France (A.V., C.D., B.C., E.M.); Inserm, UMR-S769, Châtenay-Malabry, France (A.V., C.D., B.C., E.M.); CNRS UPR 3572, IBMC, Strasbourg, Faculty of Pharmacy, France, Strasbourg, France (J.-N.S., P.S.-S.); and Inserm, U1046, Université Montpellier 1, Université Montpellier 2, CHRU Montpellier, Montpellier, France (O.C.). Frank.Lezoualch@inserm.fr.
Abstract
BACKGROUND: Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. METHODS AND RESULTS: Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin(-/-)) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constriction-induced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca(2+)/calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. CONCLUSIONS: Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca(2+)/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.
BACKGROUND:Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. METHODS AND RESULTS: Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and humanheart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin(-/-)) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constriction-induced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca(2+)/calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. CONCLUSIONS: Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca(2+)/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.
Authors: Cornelia Volland; Sebastian Bremer; Kristian Hellenkamp; Nico Hartmann; Nataliya Dybkova; Sara Khadjeh; Anna Kutschenko; David Liebetanz; Stefan Wagner; Bernhard Unsöld; Michael Didié; Karl Toischer; Samuel Sossalla; Gerd Hasenfuß; Tim Seidler Journal: Sci Rep Date: 2016-09-26 Impact factor: 4.379