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dc.contributor.authorOrtiz-Sanchez, Paula 
dc.contributor.authorVillalba-Orero, Maria 
dc.contributor.authorLopez-Olaneta, Marina 
dc.contributor.authorLarrasa-Alonso, Javier 
dc.contributor.authorSanchez-Cabo, Fatima 
dc.contributor.authorMarti-Gomez, Carlos 
dc.contributor.authorCamafeita, Emilio 
dc.contributor.authorGomez-Salinero, Jesus M. 
dc.contributor.authorRamos-Hernandez, Laura 
dc.contributor.authorNielsen, Peter J
dc.contributor.authorVazquez, Jesus 
dc.contributor.authorMüller-McNicoll, Michaela
dc.contributor.authorGarcía-Pavía, Pablo
dc.contributor.authorLara-Pezzi, Enrique 
dc.date.accessioned2019-07-30T09:18:46Z
dc.date.available2019-07-30T09:18:46Z
dc.date.issued2019-07-05
dc.identifier.citationCirc Res. 2019; 125(2):170-183es_ES
dc.identifier.issn0009-7330es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7996
dc.description.abstractRATIONALE: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. OBJECTIVE: To investigate the role of SRSF3 in cardiac function. METHODS AND RESULTS: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. CONCLUSIONS: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.es_ES
dc.description.sponsorshipThis study was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-ITN-608027 to E.L-P.), from the Spanish Ministerio de Economía y Competitividad (RTI2018-096961-BI00, SAF2015-65722-R and SAF2012-31451 to E.L-P.; BIO2015-67580-P and PGC2018-097019-B-I00 to J.V.), the Spanish Carlos III Institute of Health (CPII14/00027 to E.L-P, RD12/0042/066 to P.G.-P. and E.L-P, and RD12/0042/0056, PRB2-IPT13/0001-ISCIII-SGEFI/FEDER, ProteoRed to J.V.), the Madrid Regional Government (2010-BMD-2321 “Fibroteam” to E.L-P.). This study was also supported by the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund (ERDF) “A way of making Europe”, Spain. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).es_ES
dc.language.isoenges_ES
dc.publisherAmerican Heart Association (AHA) es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAlternative splicinges_ES
dc.subjectmRNA decappinges_ES
dc.subjectMyocardial contractiones_ES
dc.subjectMyocardial infarctiones_ES
dc.subjectPhosphorylationes_ES
dc.titleLoss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunctiones_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID31145021es_ES
dc.format.volume125es_ES
dc.format.number2es_ES
dc.format.page170-183es_ES
dc.identifier.doi10.1161/CIRCRESAHA.118.314515es_ES
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.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.contributor.funderFundación ProCNIC 
dc.description.peerreviewedes_ES
dc.identifier.e-issn1524-4571es_ES
dc.relation.publisherversionhttps://doi.org/10.1161/CIRCRESAHA.118.314515es_ES
dc.identifier.journalCirculation researches_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiacaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Proteómica cardiovasculares_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómicaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/289600/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/608027/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RTI2018-096961-BI00es_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/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/RD12/0042/0056es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PRB2-IPT13/0001es_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional