title: Carabin protects against cardiac hypertrophy by blocking calcineurin, Ras, and Ca2+/calmodulin-dependent protein kinase II signaling.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.affiliation: 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.).
authors.forename: Magali
authors.initials: M
authors.lastname: Berthouze-Duquesnes
authors.affiliation: 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.).
authors.forename: Magali
authors.initials: M
authors.lastname: Breckler
authors.affiliation: 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.).
authors.forename: Florence
authors.initials: F
authors.lastname: Tortosa
authors.affiliation: 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.).
authors.forename: Loubina
authors.initials: L
authors.lastname: Fazal
authors.affiliation: 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.).
authors.forename: Annélie
authors.initials: A
authors.lastname: de Régibus
authors.affiliation: 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.).
authors.forename: Anne-Coline
authors.initials: AC
authors.lastname: Laurent
authors.affiliation: 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.).
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.affiliation: 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.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lucas
authors.affiliation: 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.).
authors.forename: Maxime
authors.initials: M
authors.lastname: Branchereau
authors.affiliation: 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.).
authors.forename: Pauline
authors.initials: P
authors.lastname: Marck
authors.affiliation: 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.).
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: 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.).
authors.forename: Claudine
authors.initials: C
authors.lastname: Deloménie
authors.affiliation: 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.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: 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.).
authors.forename: Pauline
authors.initials: P
authors.lastname: Soulas-Sprauel
authors.affiliation: 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.).
authors.forename: Bertrand
authors.initials: B
authors.lastname: Crozatier
authors.affiliation: 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.).
authors.forename: Eric
authors.initials: E
authors.lastname: Morel
authors.affiliation: 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.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D005260:Female; D020690:GTPase-Activating Proteins / Q000096:biosynthesis*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020690:GTPase-Activating Proteins; C580816:TBC1D10C protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin
keywords: heart failure; hypertrophy; signal transduction; ventricular remodeling