Effects of Pharmacologically Induced Hyper-Protein O-GlcNAcylation on the Heart Transcriptome

Background/Objectives: O-GlcNAcylation is a post-translational modification affecting diverse cell functions, including transcriptional regulation. Aberrant levels of protein O-GlcNAcylation have been observed in neurodegenerative and cardiovascular diseases. We have previously demonstrated that systemic elevation of protein O-GlcNAcylation significantly impacted the brain transcriptome. Method: In the current study, we investigated the impact of acute inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modification from proteins using a pharmacological inhibitor, on the heart transcriptome. Results: RNA sequencing analysis detected differentially expressed genes in response to treatment with thiamet G (TG), a selective inhibitor of OGA. Pathway enrichment analysis showed oxidative phosphorylation as the top upregulated pathway, while the top downregulated pathway was related to ECM–receptor interactions. As the O-GlcNAcylation pathway is prevalent in many tissues, we hypothesized that systemic pharmacological inhibition of OGA would have a similar impact on gene regulation in the heart and brain. To test this, we compared the TG-dependent changes in the heart transcriptomes with our findings in the brain. We found overlapping differentially expressed genes associated with extracellular matrix remodeling and Alzheimer’s disease-related pathways, while metabolism, including the oxidative phosphorylation pathways, is unique to the heart. Conclusions: These studies provide new insights into the impact of acute pharmacological modulation of OGA on gene expression across the brain and heart.