RT Journal Article
T1 The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy
A1 Larrasa-Alonso, Javier
A1 Martí-Gómez, Carlos
A1 López-Olañeta, Marina M.
A1 Rey-Martín, M. Ascensión
A1 Sánchez-Cabo, Fátima
A1 McNicoll, François
A1 Müller-McNicoll, Michaela
A1 García-Pavía, Pablo
A1 Lara-Pezzi, Enrique
A1 Villalba Orero, María
A1 Ortiz Sánchez, Paula
AB 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-nucleotide-resolution 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.
SN 0009-7330
SN 1524-4571
YR 2021
FD 2021-09-03
LK https://hdl.handle.net/20.500.14352/96820
UL https://hdl.handle.net/20.500.14352/96820
LA eng
NO Larrasa-Alonso, J., Villalba-Orero, M., Martí-Gómez, C., Ortiz-Sánchez, P., López-Olañeta, M. M., Rey-Martín, M. A., Sánchez-Cabo, F., McNicoll, F., Müller-McNicoll, M., García-Pavía, P., & Lara-Pezzi, E. (2021). The SRSF4-GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy. Circulation research, 129(6), 669–683. https://doi.org/10.1161/CIRCRESAHA.120.318577
NO European Union
NO Ministerio de Economía y Competitividad
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
NO Plan Estatal I+D+I 2013-2016
NO Ministerio de Ciencia, Innovación y Universidades
NO Fundación  Pro-CNIC
NO Severo Ochoa Center de Excellence
DS Docta Complutense
RD 14 dic 2025