The mechanisms of inhibitory actions of gliclazide on neutrophils–endothelial cells adhesion and surface expression of endothelial adhesion molecules mediated by a high glucose concentration

• Published in: Journal of diabetes and its complications Vol. 17; no. 1; pp. 22 - 26
• Main Authors: Itoh, Makoto, Omi, Hitoshi, Okouchi, Masahiro, Imaeda, Kenro, Shimizu, Manabu, Fukutomi, Tatsuya, Okayama, Naotsuka
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 2003; Elsevier Science; Elsevier Limited
• Subjects: Biological and medical sciences; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Adhesion Molecules - analysis; Cells; Cells, Cultured; Diabetes; E-selectin; E-Selectin - analysis; Endothelium, Vascular - chemistry; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzymes; General and cellular metabolism. Vitamins; Gliclazide - pharmacology; Glucose - administration & dosage; Humans; Hypoglycemic Agents - pharmacology; Intercellular adhesion molecule-1; Intercellular Adhesion Molecule-1 - analysis; Kinases; Medical sciences; Neutrophils - drug effects; Neutrophils - physiology; P-selectin; P-Selectin - analysis; Pharmacology. Drug treatments; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Umbilical Veins; E-selectin; Protein kinase C; P-selectin; Intercellular adhesion molecule-1; Cell culture; Endothelial cell; E Selectin; Cardiovascular disease; Glucose; Vascular disease; Hypoglycemic agent; Atherosclerosis; Mechanism of action; Human; Healthy subject; Intercellular adhesion molecule 1; Enzyme; Transferases; Cell adhesion molecule; Experimental study; Gene expression; Biological activity; P Selectin; Treatment; Sulfonylureas; Gliclazide
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/S1056-8727(01)00219-7

Background: We previously reported that culture of endothelial cells in the presence of high glucose concentrations (27.8 and 55.5 mM) increase neutrophils adhesion because of the increase in endothelial adhesion molecules expression via activation of a protein kinase C (PKC) pathway. The antidiabetic sulfonylurea gliclazide, but not glibenclamide, inhibited these events, but the mechanisms involved were not clarified then. We present hereafter the results of further investigations of that effect with special reference to PKC activation. Methods: Human umbilical vein endothelial cells (HUVEC) were cultured for 48 h in a 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 the surface expression of endothelial adhesion molecules was determined by enzyme immunoassay. Results: Culture in the presence of a high glucose concentration (27.8 mM for 48 h) increased neutrophils–endothelial cells adhesion and the surface expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin on the endothelial cells. These phenomena were significantly inhibited by gliclazide (20 μM). On the other hand, phorbol 12-myristate 13-acetate (PMA), a PKC activator, had an effect similar to a high glucose concentration and that effect was also inhibited by gliclazide. Conclusions: These data suggest that gliclazide inhibits high glucose-mediated neutrophils–endothelial cells adhesion and expression of endothelial adhesion molecules through inhibition of a PKC pathway.