title: Asymmetrical cross-talk between the endoplasmic reticulum stress and oxidative stress caused by dextrose.
abstract: OBJECTIVE
  Oxidative and endoplasmic reticulum (ER) stresses are implicated in premature cardiovascular disease in people with diabetes. The aim of the present study was to characterize the nature of the interplay between the oxidative and ER stresses to facilitate the development of therapeutic agents that can ameliorate these stresses.
  
  
  METHODS
  Human coronary artery endothelial cells were treated with varying concentrations of dextrose in the presence or absence of three antioxidants (alpha tocopherol, ascorbate and ebselen) and two ER stress modifiers (ERSMs) (4-phenylbutyrate and taurodeoxycholic acid). ER stress was measured using the placental alkaline phosphatase assay and superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence.
  
  
  RESULTS
  The SO generation was increased with increasing concentrations of dextrose. The ER stress was increased with both low (0 and 2.75 mM) and high (13.75 and 27.5 mM) concentrations of dextrose. The antioxidants inhibited the dextrose induced SO production while in high concentrations they aggravated ER stress. The ERSM reduced ER stress and potentiated the efficacy of the three antioxidants. Tunicamycin-induced ER stress was not associated with increased SO generation. Time course experiments with a high concentration of dextrose or by overexpressing glucose transporter one in endothelial cells revealed that dextrose induced SO generation undergoes adaptive down regulation within 2 h while the ER stress is sustained throughout 72 h of observation.
  
  
  CONCLUSIONS
  The nature of the cross talk between oxidative stress and ER stress induced by dextrose may explain the failure of antioxidant therapy in reducing diabetes complications.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States. Electronic address: arshag.mooradian@jax.ufl.edu.
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Onstead-Haas
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D020239:Receptor Cross-Talk / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014415:Tunicamycin / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D013481:Superoxides; D014415:Tunicamycin; D000469:Alkaline Phosphatase; D005947:Glucose
keywords: Antioxidants; Endoplasmic reticulum stress; Endothelial cells; Hyperglycemia; Oxidative stress