Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

International Journal of Molecular Sciences

卷:21

Thenappan Thenappan¹  SashaZ. Prisco¹  Megan Eklund¹  Lauren Rose¹  Lynn Hartweck¹  KurtW. Prins¹  Francois Potus²  Danchen Wu²  Ruaa Al-Qazazi²  StephenL. Archer²  Monica Neuber-Hess²  Lian Tian²  Steven Hsu³ 

[1] Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA;

[2] Department of Medicine, Queen’s University, Kingston, ON K7L3N6, Canada;

[3] Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA;

关键词: right ventricle;    pulmonary hypertension;    metabolism;    post-translational modification;    mitochondria;   

DOI  :  10.3390/ijms21197278

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown