The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy

Author:

Larrasa-Alonso Javier1,Villalba-Orero María12,Martí-Gómez Carlos1,Ortiz-Sánchez Paula1,López-Olañeta Marina M.1,Rey-Martín M. Ascensión1,Sánchez-Cabo Fátima1,McNicoll François3ORCID,Müller-McNicoll Michaela3ORCID,García-Pavía Pablo245ORCID,Lara-Pezzi Enrique12ORCID

Affiliation:

1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.L.-A., M.V.-O., C.M.-G., P.O.S., M.M.L.-O., M.A.R.-M., F.S.C., E.L.-P.).

2. Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain (M.V.-O., P.G.-P., E.L.-P.).

3. Goethe University Frankfurt, Institute of Molecular Biosciences, Frankfurt/Main, Germany (F.M., M.M.-M.).

4. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain (P.G.-P.).

5. Facultad de Ciencias de la Salud, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain (P.G.-P.).

Abstract

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.

Funder

Ministerio de Ciencia, Innovación y Universidades

Ministerio de Economía y Competitividad

MEC | Instituto de Salud Carlos III

Comunidad de Madrid

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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