title: Participation of high glucose concentrations in neutrophil adhesion and surface expression of adhesion molecules on cultured human endothelial cells: effect of antidiabetic medicines.
abstract: BACKGROUND
  Atherosclerosis and vascular inflammation induced by hyperglycemia are important factors in the promotion of diabetic complications. One of the earliest events in the inflammatory process is increased binding of neutrophils to endothelial cells. Since vascular inflammation has been recently reported to be crucial for the onset of atherosclerosis-mediated serious diseases (acute myocardial infarction, stroke), in this study, we examined the effects of high glucose concentrations on endothelial-neutrophil cell adhesion and surface expression of endothelial adhesion molecules. We also evaluated the effects of various antidiabetic medicines on these events.
  
  
  METHODS
  Human umbilical vein endothelial cells (HUVECs) were first cultured for 48 h in the glucose-rich medium, and neutrophils from healthy volunteers were then added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring myeloperoxidase (MPO) activities, and surface expression of endothelial adhesion molecules was determined using an enzyme immunoassay.
  
  
  RESULTS
  High glucose concentrations (over 27.8 mM) increased endothelial-neutrophil cell adhesion and expression of endothelial adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin). These events were protein kinase C (PKC) dependent, because PKC inhibitors, but not other intracellular second messenger inhibitors, significantly blocked them. Among antidiabetic medicines, a sulfonylurea, gliclazide (but not glibenclamide or glimepiride), and an aldose reductase inhibitor, epalrestat, significantly inhibited these events; however, a new K(ATP)-channel blocker, netegulinide, a biguanide, metformine, or an insulin sensitizer, troglitazone, did not.
  
  
  CONCLUSIONS
  Our data is consistent with hyperglycemia-mediated vascular inflammation through increases in neutrophil adhesion and expression of endothelial adhesion molecules. These events might lead to the onset of atherosclerosis-mediated serious diseases, but could be inhibited by something perhaps, such as gliclazide and epalrestat.
authors.affiliation: First Department of Internal Medicine, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. hitoshia@med,nogoya-cu.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Omi
authors.forename: Naotsuka
authors.initials: N
authors.lastname: Okayama
authors.forename: Manabu
authors.initials: M
authors.lastname: Shimizu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okouchi
authors.forename: Shigenori
authors.initials: S
authors.lastname: Ito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Makoto
authors.initials: M
authors.lastname: Itoh
mesh_terms: D002227:Carbazoles / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D014471:Umbilical Veins
chemical_list: D002227:Carbazoles; D019040:E-Selectin; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; C081021:Go 6976; D009195:Peroxidase; D011493:Protein Kinase C; D005947:Glucose