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Authordc.contributor.authorDurán, Javier 
Authordc.contributor.authorLagos, Daniel 
Authordc.contributor.authorPavez, Mario 
Authordc.contributor.authorTroncoso, Mayarling F. 
Authordc.contributor.authorRamos, Sebastián 
Authordc.contributor.authorBarrientos Briones, Genaro 
Authordc.contributor.authorIbarra, Cristián 
Authordc.contributor.authorLavandero González, Sergio
Authordc.contributor.authorEstrada Hormazábal, Manuel 
Cita de ítemdc.identifier.citationFront. Pharmacol. 8:604es_ES
Abstractdc.description.abstractTestosterone is known to induce cardiac hypertrophy through androgen receptor (AR)-dependent and -independent pathways, but the molecular underpinnings of the androgen action remain poorly understood. Previous work has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and myocyte-enhancer factor 2 (MEF2) play key roles in promoting cardiac myocyte growth. In order to gain mechanistic insights into the action of androgens on the heart, we investigated how testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy by performing studies on cultured rat cardiac myocytes and hearts obtained from adult male orchiectomized (ORX) rats. In cardiac myocytes, MEF2 activity was monitored using a luciferase reporter plasmid, and the effects of CaMKII and AR signaling pathways on MEF2C were examined by using siRNAs and pharmacological inhibitors targeting these two pathways. In the in vivo studies, ORX rats were randomly assigned to groups that were administered vehicle or testosterone (125 for 5 weeks, and plasma testosterone concentrations were determined using ELISA. Cardiac hypertrophy was evaluated by measuring well-characterized hypertrophy markers. Moreover, western blotting was used to assess CaMKII and phospholamban (PLN) phosphorylation, and MEF2C and AR protein levels in extracts of left-ventricle tissue from control and testosterone-treated ORX rats. Whereas testosterone treatment increased the phosphorylation levels of CaMKII (Thr286) and phospholambam (PLN) (Thr17) in cardiac myocytes in a time-and concentration-dependent manner, testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were prevented upon inhibition of CaMKII, MEF2C, and AR signaling pathways. Notably, in the hypertrophied hearts obtained from testosterone-administered ORX rats, both CaMKII and PLN phosphorylation levels and AR and MEF2 protein levels were increased. Thus, this study presents the first evidence indicating that testosterone activates MEF2 through CaMKII and AR signaling. Our findings suggest that an orchestrated mechanism of action involving signal transduction and transcription pathways underlies testosterone-induced cardiac myocyte hypertrophy.es_ES
Patrocinadordc.description.sponsorshipFondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1120259 151118 Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP) from de Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), Chile 15130011es_ES
Publisherdc.publisherFrontiers media SAes_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.uri*
Sourcedc.sourceFrontiers in Pharmacologyes_ES
Keywordsdc.subjectAndrogen receptores_ES
Keywordsdc.subjectCardiac myocytees_ES
Títulodc.titleCa2+/ Calmodulin dependent protein kinase II and androgen signaling pathways modulate MEF2 activity in testosterone induced cardiac myocyte hypertrophyes_ES
Document typedc.typeArtículo de revista
Indexationuchile.indexArtículo de publicación ISIes_ES

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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile