Abstract 261: G3bp1-Gas5 Axis Regulates Glucocorticoid Receptor Signaling During Cardiac Hypertrophy

Abstract

Congestive heart failure is one of the leading causes of mortality in US. With persistent work overload, pathological hypertrophy progresses into an irreversible state of dysfunction and failure. Understanding the mechanisms involved in these advances is crucial to prevent adverse changes in the heart. Studies show that Glucocorticoid (Gc) signaling and -dependent gene transcription promotes cardiac hypertrophy and fibrosis. High serum cortisol levels have been shown as independent risk factor for increased mortality in patients with cardiac failure. Gc activates cytosolic Glucocorticoid receptor (GR) that translocates to nucleus and regulates gene transcription by binding to genomic GR-response element (GRE). We confirmed nuclear translocation of GR in hypertrophing cardiac myocytes in vitro and in vivo . Our aim was to examine GR signaling in cardiac myocytes. Using in vitro biotin labeling and RNA immunoprecipitation we show that a non-coding RNA Gas5, which harbors decoy GRE sequence associates with GR in cardiac myocytes and competes with genomic GRE for DNA binding domain of GR, thus inhibiting the transcriptional effects of activated GR. Interestingly, this association decreases with hypertrophy or Gc agonist (dexamethasone) stimulation. Conversely, Gas5 association with G3bp1, a RNA binding protein increases in cardiac myocytes with similar stimulations, suggesting that increase in G3bp1-Gas5 binding might play a role in release of activated GR from Gas5. In accordance, expression of exogenous Gas5 in vitro and in vivo restricted hypertrophy, suggesting critical role in progression of hypertrophy. We recently reported that G3bp1 is required for development of cardiac hypertrophy. Moreover, in situ hybridization revealed sequestration of Gas5 transcripts to perinuclear focal regions with growth stimulus, which resemble cytoplasmic protein-RNA aggregates seen with hypertrophic stimulation or G3bp1 over expression in cardiac myocytes. These results suggest that G3bp1 regulates Gas5 cellular compartmental dynamics and hence its GR-repressor function in cardiac myocytes. Thus, we conclude that G3bp1-Gas5 axis regulates GR -dependent gene transcription and progression of pathological cardiac hypertrophy and onset of failure