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dc.contributor.authorPadron-Barthe, Laura 
dc.contributor.authorVillalba-Orero, Maria 
dc.contributor.authorGomez-Salinero, Jesus M. 
dc.contributor.authorAcin-Perez, Rebeca 
dc.contributor.authorCogliati, Sara 
dc.contributor.authorLopez-Olaneta, Marina 
dc.contributor.authorOrtiz-Sanchez, Paula 
dc.contributor.authorBonzon-Kulichenko, Elena 
dc.contributor.authorVazquez, Jesus 
dc.contributor.authorGarcia-Pavia, Pablo 
dc.contributor.authorRosenthal, Nadia
dc.contributor.authorEnriquez, Jose Antonio 
dc.contributor.authorLara-Pezzi, Enrique 
dc.date.accessioned2018-11-22T08:10:53Z
dc.date.available2018-11-22T08:10:53Z
dc.date.issued2018
dc.identifierISI:000424512200009
dc.identifier.citationJ Am Coll Cardiol. 2018; 71(6):654-667
dc.identifier.issn0735-1097
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6687
dc.description.abstractBACKGROUND In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. OBJECTIVES The authors aimed to determine the role of the calcineurin splicing variant CnA beta 1 in the context of cardiac hypertrophy and its mechanism of action. METHODS Transgenic mice overexpressing CnAb1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnA beta 1 (CnA beta 1(Delta i12) mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. RESULTS In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnA beta 1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAb1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnA beta 1. CnA beta 1(Delta i12) mice show increased cardiac hypertrophy and declined contractility. CONCLUSIONS The metabolic reprogramming induced by CnAb1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches. (J Am Coll Cardiol 2018; 71: 654-67) (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
dc.description.sponsorshipThis work was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-608027 to Dr. Lara-Pezzi; Meet-ITN-317433 to Dr. Enriquez; UE0/MCA1108 to Dr. Acin-Perez), from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R and SAF2012-31451 to Dr. Lara-Pezzi; SAF2015-71521-REDC, BFU2013-50448, and SAF2012-32776 to Dr. Enriquez; RyC-2011-07826 to Dr. Acin-Perez; BIO2012-37926 and BIO2015-67580-P to Dr. Vazquez), from the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi; RD12/0042/066 to Drs. Garcia-Pavia and Lara-Pezzi), from the Regional Government of Madrid (2010-BMD-2321 ``Fibroteam´´ to Dr. Lara-Pezzi; 2011-BMD-2402 ``Mitolab´´ to Dr. Enriquez) and the FIS-ISCIII (PRB2-IPT13/0001 and RD12/0042/0056-RIC-RETICS to Dr. Vazquez). This work was also supported by the Plan Estatal de IthornDthornI 2013-2016-European Regional Development Fund (FEDER) ``A way of making Europe,´´ Spain. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and by the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Drs. Vazquez and Garcia-Pavia have served as consultants for VL39. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Padron-Barthe, Villalba-Orero, and Gomez-Salinero contributed equally to this work and are joint first authors. Robyn Shaw, MD, PhD, served as Guest Editor for this paper.
dc.language.isoeng
dc.publisherElsevier 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectCardiac function
dc.subjectCell signaling
dc.subjectHypertrophy
dc.subjectMetabolism
dc.titleActivation of Serine One-Carbon Metabolism by Calcineurin A beta 1 Reduces Myocardial Hypertrophy and Improves Ventricular Function
dc.typejournal article
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID29420962
dc.format.volume71
dc.format.page654-667
dc.identifier.doi10.1016/j.jacc.2017.11.067
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderFundación ProCNIC 
dc.description.peerreviewed
dc.identifier.e-issn1558-3597
dc.relation.publisherversionhttps://doi.org/10.1016/j.jacc.2017.11.067
dc.identifier.journalJournal of the American College of Cardiology
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiaca
dc.repisalud.orgCNICCNIC::Grupos de investigación::Genética Funcional del Sistema de Fosforilación Oxidativa
dc.repisalud.orgCNICCNIC::Grupos de investigación::Proteómica cardiovascular
dc.repisalud.institucionCNIC
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2015-65722-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2012-31451es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2015-71521-REDCes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2013-50448es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2012-32776es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RyC-2011-07826es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BIO2012-37926es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BIO2015-67580-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CPII14/00027es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/066es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PRB2-IPT13/0001es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0056es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/289600/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/317433/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/608027/EUes_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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