Protective actions of gliclazide on high insulin-enhanced neutrophil–endothelial cell interactions through inhibition of mitogen activated protein kinase and protein kinase C pathways

• Published in: Microvascular Research Vol. 67; no. 1; pp. 1 - 8
• Main Authors: Okouchi, Masahiro, Okayama, Naotsuka, Omi, Hitoshi, Imaeda, Kenro, Fukutomi, Tatsuya, Nakamura, Atsushi, Itoh, Makoto
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 2004
• Subjects: Atherosclerosis; Cell Adhesion; Cells, Cultured; Diabetes; Diabetes Mellitus - drug therapy; Endothelial Cells - drug effects; Endothelium, Vascular - cytology; Gliclazide - pharmacology; Humans; Hyperinsulinemia; Hypoglycemic Agents - pharmacology; Immunoenzyme Techniques; Insulin - metabolism; Insulin resistance; Intercellular Adhesion Molecule-1 - metabolism; MAP Kinase Signaling System; Neutrophils - drug effects; Neutrophils - metabolism; Nitric Oxide - metabolism; Potassium Channels - metabolism; Protein Kinase C - antagonists & inhibitors; Umbilical Veins - cytology; Vascular inflammation; Hyperinsulinemia; Insulin resistance; Diabetes; Vascular inflammation; Atherosclerosis
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2003.09.008

Background and aim: There are many lines of evidence indicating that hyperinsulinemia but not hyperglycemia is linked to the development of atherosclerotic diseases such as coronary events in diabetic patients. K ATP channel blockers of the sulphonylurea class are used widely to treat type 2 diabetes mellitus even with hyperinsulinemia. In this study, we determined whether K ATP channel blockers can protect against atherosclerotic processes enhanced by hyperinsulinemia, namely leukocyte–endothelial cell interactions. In addition, we characterized the intracellular mechanisms involved in protective actions of the K ATP channel blocker(s). Method: Studies of adhesion between neutrophils and human umbilical vein endothelial cells incubated in insulin-rich medium with or without K ATP channel blockers were performed. Adhered neutrophils were quantified by measuring their myeloperoxidase activities, and surface expression of endothelial ICAM-1 was examined using an enzyme immunoassay. Results: Both neutrophil adhesion and ICAM-1 expression enhanced by high insulin (100 μU/ml, 48 h) were attenuated by gliclazide (20 μM), but not by other K ATP channel blockers (glibenclamide, nateglinide, and glimepiride). In addition, both neutrophil adhesion and ICAM-1 expression which were increased by a MAP kinase activator, anisomycin (1 μM), or a PKC activator, phorbol 12-myristate 13-acetate (10 nM) were also attenuated by gliclazide. Nitric oxide (NO) synthase inhibitors did not affect these effects of gliclazide. Conclusions: These results suggest that among K ATP channel blockers, only gliclazide can act directly on endothelial cells to inhibit neutrophil–endothelial cell adhesion and ICAM-1 expression enhanced by hyperinsulinemia. These effects of gliclazide are mediated through inhibiting activation of MAP kinase and PKC, unrelated to NO production.