title: p38 Mitogen-activated protein kinase is required for glucosamine-induced endothelial nitric oxide synthase uncoupling and plasminogen-activator inhibitor expression.
abstract: BACKGROUND
  Hexosamine biosynthetic pathway (HBP) is implicated in increased plasminogen activator inhibitor-1 (PAI-1), and endothelial nitric oxide synthase (eNOS) dysfunction in diabetes. Glucosamine (GlcN) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models. p38 mitogen-activated protein kinase (p38mapk) has been shown to be involved in HBP-mediated biological processes. The aim of the present study was to investigate the role of p38mapk in GlcN-induced endothelial PAI-1 expression and eNOS dysfunction.
  
  
  RESULTS
  In cultured human endothelial cells, GlcN time- and concentration-dependently increased PAI-1 protein level that was further enhanced by tumor necrosis factor (TNF)-α, which was accompanied by a transient synergistic activation of p38mapk. The stimulation of PAI-1 by GlcN alone or by GlcN and TNF-α in combination was inhibited by the specific inhibitor of p38mapk, but not that of JNK or ERK1/2. Moreover, in isolated mouse aortas, GlcN caused eNOS uncoupling resulting in enhanced superoxide and decreased NO production, as well as impaired endothelium-dependent relaxations, which were also fully prevented by the p38mapk inhibitor.
  
  
  CONCLUSIONS
  HBP activated by GlcN increases PAI-1 expression and eNOS uncoupling depending on p38mapk, which not only explains hyperglycemic vascular complications, but also may bring into question the clinical use of GlcN. The present results, support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease.
authors.affiliation: Department of Medicine, Division of Physiology, University of Fribourg, Switzerland.
authors.forename: Zongsong
authors.initials: Z
authors.lastname: Wu
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Thusitha
authors.initials: T
authors.lastname: Gajanayake
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005944:Glucosamine / Q000009:adverse effects* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D005944:Glucosamine