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dc.contributor.authorTorrado, Mario
dc.contributor.authorIglesias, Raquel
dc.contributor.authorCenteno Cortés, Alberto 
dc.contributor.authorLópez Pelaez, Eduardo
dc.contributor.authorMikhailov, Alexander T
dc.date.accessioned2017-06-07T07:09:06Z
dc.date.available2017-06-07T07:09:06Z
dc.date.issued2011
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/20.500.11940/3157
dc.description.abstractBACKGROUND: Myocardin (MYOCD), a potent transcriptional coactivator of smooth muscle (SM) and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF). However, the molecular and functional consequences of myocd upregulation in HF are still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox)-induced diastolic HF (DHF) model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV) myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1) a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2) amelioration of impaired diastolic dysfunction, and (3) higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery) led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function. CONCLUSIONS/SIGNIFICANCE: These data provide the first evidence that a moderate inhibition (e.g., normalization) of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view.
dc.language.isoeng
dc.rightsAtribución 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.meshHeart Failure, Diastolic
dc.subject.meshMolecular Sequence Data
dc.subject.meshMuscle, Smooth
dc.subject.meshSignal Transduction
dc.subject.meshGene Silencing
dc.subject.meshSilenciador del Gen
dc.titleTargeted gene-silencing reveals the functional significance of myocardin signaling in the failing heart
dc.typeArtigoes
dc.authorsophosTorrado, M.
dc.authorsophosIglesias, R.
dc.authorsophosCenteno, A.
dc.authorsophosLópez, E.
dc.authorsophosMikhailov, A. T.
dc.identifier.doi10.1371/journal.pone.0026392
dc.identifier.isi296186900058
dc.identifier.pmid22028870
dc.identifier.sophos9433
dc.issue.number10
dc.journal.titlePLoS One
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de A Coruña::INIBIC.- Instituto de Investigación Biomédica
dc.rights.accessRightsopenAccess
dc.subject.decsInsuficiencia Cardíaca Diastólica
dc.subject.decsDatos de Secuencia Molecular
dc.subject.decsMúsculo Liso
dc.subject.decsTransducción de Señal
dc.typesophosArtículo Original
dc.volume.number6


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