Key result
Colchicine-mediated AMP-kinase activation reduced O-GlcNAcylation and improved right ventricular function in monocrotaline rats, suggesting excess O-GlcNAcylation contributes to RV dysfunction.
Why the study?
While studies show increased right ventricular glucose uptake in pulmonary arterial hypertension, the relationship between O-GlcNAcylation and right ventricular function remained unexplored.
Does colchicine-mediated AMP-kinase activation improve right ventricular function by reducing O-GlcNAcylation in pulmonary arterial hypertension?
Does colchicine-mediated AMP-kinase activation improve right ventricular function by reducing O-GlcNAcylation in pulmonary arterial hypertension?
Excess O-GlcNAcylation contributes to metabolic derangements and right ventricular dysfunction in pulmonary arterial hypertension, highlighting a potential novel therapeutic target.
Hypothesis-generating in PAH; leaves open O-GlcNAcylation inhibition as a target pending human trials.
-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH.
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Prisco et al. (2020) studied Pulmonary Arterial Hypertension. Colchicine-mediated AMP-kinase activation was evaluated on Right ventricular function and O-GlcNAcylation levels. Colchicine-mediated AMP-kinase activation reduced O-GlcNAcylation and improved right ventricular function in monocrotaline rats, suggesting excess O-GlcNAcylation contributes to RV dysfunction.
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