Congestive heart failure due to conditions like hypertension, metabolic syndrome, and other systemic conditions have shown no improvement in death rates over the years and is one of the leading cause of mortality in US. With persistent work overload, pathological cardiac hypertrophy progresses into an irreversible state of dysfunction and failure. Therefore, understanding the mechanisms involved in these advances is crucial for developing new therapeutic targets to prevent the adverse changes in the heart. Adaptive changes in gene expression are one of the fundamental responses of heart to hypertrophic stress stimulus, which is orchestrated by transcriptional and posttranscriptional gene regulation. Studies have implicated stress hormone Glucocorticoid (Gc) signaling and -dependent gene transcription in promoting hypertrophy and cardiac fibrosis. High serum cortisol levels have been identified as independent risk factor for increased mortality in patients with cardiac failure. Gc activates cytosolic Glucocorticoid receptor (GR) that translocates to nucleus and regulates specific gene transcription by binding to GR-response element (GRE). Studies in cancer cells have shown that a non-coding RNA, Gas5 harbors decoy GRE sequence (GREm) in its stem-loop secondary structure and competes with genomic GRE for DNA binding domain of GR, thus inhibiting the transcriptional effects of activated GR. Our preliminary data shows similar Gas5-GR association in cardiac myocytes, which decreases with hypertrophic or Glucocorticoid agonist (dexamethasone) stimulation. Conversely, Gas5 association with G3bp1, a RNA binding protein (RBP) 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 for its downstream transcriptional effects. G3bp1 is a sequence-specific RBP that can function as an endoribonuclease or mediator of protein-RNA aggregates called stress granules, depending on its phosphorylation status. Moreover, in situ hybridization revealed translocation of Gas5 transcripts to perinuclear focal regions with growth stimulus, which resemble cytoplasmic protein-RNA aggregates seen with hypertrophic stress or G3bp1 over expression in cardiac myocytes. These results suggest that G3bp1 plays a role in Gas5 dynamics within cellular compartments and regulates its function. In vivo inhibition of endogenous G3bp1 or expression of Gas5 in mice restricted TAC-induced cardiac hypertrophy, suggesting critical role in hypertrophy development. Thus we have hypothesized that dephosphylation of G3bp1 with hypertrophic growth increases its association with Gas5, which results in release of Gc-activated GR that binds to genomic GRE to mediate its effects on specific gene transcription and favors cardiac remodeling, progression of hypertrophy and onset of failure. Based on our preliminary data we have proposed three robust specific aims to test this hypothesis. 1. To determine the mechanisms by which G3bp1 regulates Gas5 function during cardiac hypertrophy. 2. To examine the role of Gas5 in regulating stress induced GR signaling and its role in regulating GRE-dependent gene transcription in hypertrophying cardiac myocytes 3. Using in vivo knockdown and overexpression mouse models of G3bp1 and Gas5 identify the role of G3bp1-Gas5-GR signaling in development of pathological cardiac hypertrophy and onset of failure.
High circulating levels of stress hormone Glucocorticoid have been identified as an independent risk factor for increased mortality due to cardiac failure. In ths project we will determine the underlying mechanisms that regulate Glucocorticoid signaling and -dependent genes transcription in cardiac myocytes during hypertrophic stress conditions. The project will reveal new therapeutic pathways that may be involved in progression of pathological cardiac hypertrophy into failure.
|Shin, Hyewon; He, Minzhen; Yang, Zhi et al. (2018) Transcriptional regulation mediated by H2A.Z via ANP32e-dependent inhibition of protein phosphatase 2A. Biochim Biophys Acta Gene Regul Mech 1861:481-496|
|He, Minzhen; Yang, Zhi; Abdellatif, Maha et al. (2015) GTPase Activating Protein (Sh3 Domain) Binding Protein 1 Regulates the Processing of MicroRNA-1 during Cardiac Hypertrophy. PLoS One 10:e0145112|