The hexosamine biosynthetic pathway (HBP) converts glucose to the monosaccharide uridine diphosphate N-acetylglucosamine (UDP-N-acetylglucoasmine). UDP-N-acetylglucoasmine can function as a signaling molecule by regulating function of multiple proteins via O-glycosidic linkage to serine or threonine residues in a process known as protein O-GlyNAcylation. While numerous studies show glucose uptake is dramatically increased in the right ventricle (RV) in pulmonary arterial hypertension (PAH), the subsequent effects on HBP and protein O-GlyNAcylation in the RV are unexplored.
Metabolomics and Western blot analysis were used to quantify UDP-N-acetylglucoasmine levels and total protein O-GlyNAcylation in control and monocrotaline (MCT) rats respectively. Echocardiography was used to characterize RV function in rats. Finally, to indirectly examine the relationship between protein O-GlyNAcylation and RV function in PAH patients, the presence of diabetes and the relationship between hemoglobin A1C (HgbA1C) and RV function was examined in non-Scleroderma PAH patients from the University of Minnesota PH clinic. Dp/dtmax/instantaneous pressure (IP) was calculated from RV pressure tracings to estimate RV contractility.
UDP-N-acetylglucoasmine is significantly elevated in the RV of MCT rats (2.4±0.8 fold increase, p<0.001) and is negatively correlated with cardiac output (r=-0.78, p<0.001) and tricuspid annular plane systolic excursion (r=-0.72, p=0.002). Total protein O-GlyNAcylation is increased in the RV (2.8±0.9 fold increase, p=0.005) but reduced in the left ventricle (0.59±0.19 fold decrease, p=0.04) of MCT rats. In PAH patients, HgbA1C is negatively correlated with dp/dtmax/IP (r=-0.48, p=0.05) and diabetic patients have a significant reduction in dp/dtmax/IP (12.5±4.8 vs 17.2±5.9 s-1, p=0.02) despite no differences in pulmonary arterial compliance (1.8±1.3 vs 1.6±1.3 mL/mm Hg, p=0.64) or pulmonary vascular resistance (8.8±5.7 vs 10.2±5.7 Wood units, p=0.31).
Elevated protein O-GlcNacylation is associated with RV dysfunction in PAH. Further studies are needed to determine if inhibition of protein O-GlcNacylation could represent a novel therapeutic strategy to improve RV function.