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dc.contributor.authorFelkin, Leanne E
dc.contributor.authorNarita, Takuya
dc.contributor.authorGermack, Renée
dc.contributor.authorShintani, Yasunori
dc.contributor.authorTakahashi, Kunihiko
dc.contributor.authorSarathchandra, Padmini
dc.contributor.authorLopez-Olaneta, Marina 
dc.contributor.authorGomez-Salinero, Jesus M. 
dc.contributor.authorSuzuki, Ken
dc.contributor.authorBarton, Paul J R
dc.contributor.authorRosenthal, Nadia
dc.contributor.authorLara-Pezzi, Enrique
dc.identifier.citationCirculation. 2011; 123(24):2838-47es_ES
dc.description.abstractBACKGROUND: Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin Aβ (CnAβ) gene generates the CnAβ1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAβ1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown. METHODS AND RESULTS: We generated transgenic mice overexpressing CnAβ1 in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAβ1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnAβ1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnAβ1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation. CONCLUSIONS: Calcineurin Aβ1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAβ1 an attractive candidate for the development of future therapeutic approaches.es_ES
dc.description.sponsorshipBritish Heart Foundation [PG/07/020/22503]; Spanish Ministry of Science and Innovation [BFU2009-10016]; National Institutes of Health Research, Cardiovascular Biomedical Research Unit at the Royal Brompton; Hare-field NHS Foundation Trust; Imperial College; Spanish Fondo Nacional de Investigaciones Sanitarias [EIF-040545, ERG-239158, CP08/00144]es_ES
dc.publisherAmerican Heart Association (AHA) es_ES
dc.subject.meshActivating Transcription Factor 4 es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshCalcineurin es_ES
dc.subject.meshCardiomegaly es_ES
dc.subject.meshFibrosis es_ES
dc.subject.meshGene Expression Profiling es_ES
dc.subject.meshHeart es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Transgenic es_ES
dc.subject.meshMyocardial Contraction es_ES
dc.subject.meshMyocardial Infarction es_ES
dc.subject.meshMyocarditis es_ES
dc.subject.meshMyocardium es_ES
dc.subject.meshMyosin Heavy Chains es_ES
dc.subject.meshProtein Isoforms es_ES
dc.subject.meshSignal Transduction es_ES
dc.titleCalcineurin splicing variant calcineurin Aβ1 improves cardiac function after myocardial infarction without inducing hypertrophyes_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderBritish Heart Foundation 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.contributor.funderNHS Foundation Trust
dc.contributor.funderImperial College London (Reino Unido) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiacaes_ES
dc.rights.accessRightsopen accesses_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional