title: Hyperglycemia-induced endoplasmic reticulum stress in endothelial cells.
abstract: OBJECTIVE
  Hyperglycemia-induced endothelial cell dysfunction in vascular disease can occur due to increased oxidative stress and a concomitant increase in endoplasmic reticulum (ER) stress. To investigate whether these cellular stresses are independent or causally linked, we determined whether or not specific glycolytic intermediates that induce oxidative stress also induce ER stress.
  
  
  METHODS
  Human umbilical vein endothelial cells were treated with dextrose, partially metabolizable (e.g., fructose and galactose) and non-metabolizable sugars (e.g., 3-O-methyglucose), and various intermediates of the glycolytic and tricarboxylic acid pathways. Activation of the unfolded protein response and subsequent generation of ER stress was measured by the ER stress-responsive alkaline phosphatase method, and superoxide (SO) generation was measured using the hydro-ethidene-fluorescence method. The mitochondrial origin of the SO and the generation of ER stress by dextrose and the intermediate metabolites were confirmed with experiments using allopurinol and diphenyleneiodonium chloride to block SO generation by xanthine oxidase and nicotinamide adenosine dinucleotide phosphate oxidase, respectively.
  
  
  RESULTS
  Although ER stress could be induced by glycolytic intermediates up to and including pyruvate, the SO generation occurred in the presence of glycolytic and mitochondrial metabolites.
  
  
  CONCLUSIONS
  Although the mitochondria are the site of signals generated by dextrose to initiate oxidative stress, the dextrose-induced ER stress, unlike SO generation, does not require pyruvate oxidation in the mitochondria.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida, Jacksonville, Florida, USA. mae.sheikh-ali@jax.ufl.edu
authors.forename: Mae
authors.initials: M
authors.lastname: Sheikh-Ali
authors.forename: Senan
authors.initials: S
authors.lastname: Sultan
authors.forename: Abdul-Razzak
authors.initials: AR
authors.lastname: Alamir
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
mesh_terms: D019325:3-O-Methylglucose / Q000009:adverse effects; D000469:Alkaline Phosphatase / Q000378:metabolism; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000378:metabolism; D005947:Glucose / Q000009:adverse effects* / Q000378:metabolism; D006019:Glycolysis; D006601:Hexoses / Q000009:adverse effects; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D008928:Mitochondria / Q000187:drug effects; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D056811:Unfolded Protein Response; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D006601:Hexoses; D013481:Superoxides; D019325:3-O-Methylglucose; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; C548269:ALPG protein, human; D000469:Alkaline Phosphatase; D005947:Glucose