TY  - JOUR
A1  - Larrasa-Alonso, Javier
A1  - Villalba-Orero, María
A1  - Martí-Gómez, Carlos
A1  - Ortiz-Sánchez, Paula
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
T1  - The SRSF4-GAS5-glucocorticoid receptor axis regulates ventricular hypertrophy
T2  - Circulation research
N2  - RATIONALE: 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-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.
KW  - left ventricular hypertrophy
KW  - RNA-binding proteins
KW  - glucocorticoid receptor
KW  - long noncoding RNA
KW  - cardiovascular disease
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63201
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-632012
SN  - 1524-4571
N1  - This study was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-ITN-608027 to E. Lara-Pezzi), from the Spanish Ministerio de Economía y Competitividad (RTI2018-096961-B-I00, SAF2015-65722-R, and SAF2012-31451 to E. Lara-Pezzi), the Spanish Carlos III Institute of Health (CPII14/00027 to E. Lara-Pezzi, RD12/0042/066 to P. García-Pavía and E. Lara-Pezzi, and RD12/0042/005), the Madrid Regional Government (2010-BMD-2321 Fibroteam to E. Lara-Pezzi). This study was also supported by the Plan Estatal de I+D+I 2013-2016, with funding from the European Regional Development Fund (ERDF) A way to build Europe initiative. 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).
N1  - The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.120.318577.
VL  - 129
IS  - 6
SP  - 669
EP  - 683
PB  - Assoc.
CY  - New York, NY
ER  -