Excess protein O-GlcNAcylation links metabolic derangements to right ventricular dysfunction in pulmonary arterial hypertension

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Prisco, Sasha Z. and Rose, Lauren and Potus, Francois and Tian, Lian and Wu, Danchen and Hartweck, Lynn and Al-Qazazi, Ruaa and Neuber-Hess, Monica and Eklund, Megan and Hsu, Steven and Thenappan, Thenappan and Archer, Stephen L. and Prins, Kurt W. (2020) Excess protein O-GlcNAcylation links metabolic derangements to right ventricular dysfunction in pulmonary arterial hypertension. International Journal of Molecular Sciences, 21 (19). 7278. ISSN 1422-0067 (https://doi.org/10.3390/ijms21197278)

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Abstract

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-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.

ORCID iDs

Prisco, Sasha Z., Rose, Lauren, Potus, Francois, Tian, Lian ORCID logoORCID: https://orcid.org/0000-0002-9699-8009, Wu, Danchen, Hartweck, Lynn, Al-Qazazi, Ruaa, Neuber-Hess, Monica, Eklund, Megan, Hsu, Steven, Thenappan, Thenappan, Archer, Stephen L. and Prins, Kurt W.;
CORE (COnnecting REpositories)