Abstract
Background: Hypertension is a leading risk factor for heart disease. Because the beta-O-linkage of N-acetylglucosamine (O-GlcNAc) post-translational modification plays a significant, pro-adaptive role in the cardiovascular system's response to various stressors, we hypothesized that this stress response (protein O-GlcNAcylation) was important in mitigating pressure overload-induced cardiac dysfunction. Methods and Results: Wild-type mice were randomly assigned to drug or vehicle groups and followed for seven days after transverse aortic constriction (TAC, i.e., pressure overload). The drug group was given TT04 (10mg/kg, bid), a specific inhibitor of O-GlcNAc transferase (the enzyme that adds O-GlcNAc to proteins). TT04 treatment significantly exacerbated systolic dysfunction (Fig 1B) despite no change in diastolic diameter (Fig 1A). TT04 treatment also diminished ejection fraction (Fig 1C) and reduced levels of protein O-GlcNAcylation (Fig 1D) compared to vehicle (p<0.05). Conclusions: O-GlcNAc signaling plays an important, seemingly pro-adaptive role in the heart during pressure overload-induced cardiac dysfunction.
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