Abstract Wed066: Modulation of YAP/TEAD1 Signaling by O-GlcNAcylation in Cardiac Hypertrophy

Elevated levels of O-beta-N-acetylglucosamine (O-GlcNAc)-modified proteins (OGN) in the heart have been linked to hypertrophy and maladaptive remodeling. OGN levels are regulated by O-GlcNAc transferase (OGT), which adds O-GlcNAc, and O-GlcNAcase (OGA), which removes it. Our prior data from animal models with myocardial overexpression of OGA/OGT suggest a novel interaction between O-GlcNAcylation and the Yes Associated Protein (YAP)/TEAD1 pathway, a key regulator of cardiac hypertrophy. Phosphorylated YAP is sequestered in the cytoplasm and targeted for degradation, while active YAP is translocated to the nucleus where it enhances TEAD1 transcriptional activity. Given this regulatory mechanism, we investigated whether increased O-GlcNAcylation activates YAP by either promoting its nuclear localization or reducing phospho-YAP/total YAP levels. Cardiomyocytes treated with phenylephrine, a pro-hypertrophic stressor, increased phospho-LATS and phospho-YAP levels, accompanied by decreased O-GlcNAc-modified protein levels. However, pre-treating cells with TMG, an agent that increases O-GlcNAcylation, restored OGN levels and increased transcriptionally active YAP, suggesting a link between O-GlcNAcylation and YAP activation. To further explore this relationship, we quantified nuclear and cytoplasmic YAP intensities in neonatal rat ventricular myocytes (NRVMs) treated to either increase O-GlcNAcylation via adenoviral-OGT or decrease it via OSMI-1 treatment. Overexpression of OGT promoted YAP nuclear localization, whereas OGT inhibition reduced nuclear YAP levels. Consistently, in a luciferase reporter assay, excess O-GlcNAcylation induced by adenoviral-OGT enhanced YAP/TEAD1 transcriptional activity. Our findings demonstrate that O-GlcNAcylation plays a crucial role in modulating YAP activity by promoting its nuclear localization and enhancing YAP/TEAD1 transcriptional activity. Our in vitro results suggest that O-GlcNAcylation acts as a regulatory mechanism in cardiac cells, modulating the activity of YAP during hypertrophic stress.