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dc.contributor.authorLarrasa-Alonso, Javier
dc.contributor.authorVillalba-Orero, María
dc.contributor.authorMartí-Gómez, Carlos
dc.contributor.authorOrtiz-Sánchez, Paula
dc.contributor.authorLópez-Olañeta, Marina M.
dc.contributor.authorRey-Martín, M. Ascensión
dc.contributor.authorSánchez-Cabo, Fátima
dc.contributor.authorMcNicoll, François
dc.contributor.authorMüller-McNicoll, Michaela
dc.contributor.authorGarcía Pavía, Pablo 
dc.contributor.authorLara-Pezzi, Enrique
dc.date.accessioned2022-03-04T12:35:47Z
dc.date.available2022-03-04T12:35:47Z
dc.date.issued2021
dc.identifier.issn0009-7330spa
dc.identifier.urihttp://hdl.handle.net/10641/2887
dc.description.abstractRATIONALE: RBPs (RNA-binding proteins) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP SRSF4 (serine/arginine-rich splicing factor 4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. OBJECTIVE: To investigate the role of SRSF4 in the heart. METHODS AND RESULTS: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotideresolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. CONCLUSIONS: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.spa
dc.language.isoengspa
dc.publisherCirculation Researchspa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subjectCardiovascular diseasespa
dc.subjectGlucocorticoid receptorspa
dc.subjectLeft ventricular hypertrophyspa
dc.subjectLong noncoding RNAspa
dc.subjectRNA-binding proteinsspa
dc.titleThe SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy.spa
dc.typearticlespa
dc.description.versionpost-printspa
dc.rights.accessRightsopenAccessspa
dc.description.extent2695 KBspa
dc.identifier.doi10.1161/CIRCRESAHA.120.318577spa
dc.relation.publisherversionhttps://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.318577spa


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