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

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

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    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.;