Excess protein o-glcnacylation links metabolic derangements to right ventricular dysfunction in pulmonary arterial hypertension

Sasha Z Prisco, Lauren Rose, Francois Potus, Lian Tian, Danchen Wu, Lynn Hartweck, Ruaa Al-Qazazi, Monica Neuber-Hess, Megan Eklund, Steven Hsu, Thenappan Thenappan, Stephen L. Archer, Kurt W Prins

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Article number7278
Pages (from-to)1-19
Number of pages19
JournalInternational journal of molecular sciences
Issue number19
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
Funding: S.Z.P. is funded by NIH T32 HL144472, a University of Minnesota Clinical and Translational Science award (NIH UL1 TR0029494), and a University of Minnesota Academic Investment Educational Program grant, S.H. is funded by NIH K23 HL146889, SLA is funded by CIHR Foundation Grant, a Tier 1 Canada Research Chair in Mitochondrial Dynamics, the Queen’s Cardiopulmonary Unit (QCPU) and the William J Henderson Foundation, and K.W.P. is funded by NIH K08 HL140100, the Cardiovascular Medical Research and Education Fund, and the Jenesis Award from United Therapeutics.

Funding Information:
Conflicts of Interest: K.W.P. received modest consultation fees from Actelion and received grant funding from United Therapeutics and T.T. received modest consultation fees from Actelion and Gilead. The other authors declared no conflict of interest exists.


  • Metabolism
  • Mitochondria
  • Post-translational modification
  • Pulmonary hypertension
  • Right ventricle


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