title: The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects.
abstract: Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-alpha (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-alpha. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-alpha. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway.
authors.affiliation: Division of Physiology, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.
authors.forename: Angana Gupta
authors.initials: AG
authors.lastname: Rajapakse
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
authors.forename: João M
authors.initials: JM
authors.lastname: Carvas
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001377:Azaserine / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D006595:Hexosamines; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; D001377:Azaserine; D013482:Superoxide Dismutase; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D005947:Glucose; D000109:Acetylcholine; D000077185:Resveratrol