title: Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway.
abstract: Diabetes mellitus is one of the major risk factors for coronary artery disease (CAD). A recent study reported that glimepiride, a new third-generation sulfonylurea, inhibited the formation of atheromatous plaques in high-cholesterol fed rabbits. However, the mechanism by which glimepiride induces atheroprotection remains unknown. In the present study, we tested the hypothesis that glimepiride may stimulate NO production in vascular endothelial cells. Human coronary artery endothelial cells (HCAECs) were treated with glimepiride, glibenclamide or vehicle, and NO release was measured. Akt phosphorylation was evaluated by Western blot. The effects of LY294002, a specific PI3-kinase inhibitor, and antisense oligonucleotides directed to Akt, on glimepiride-induced NO production were examined. Glimepiride (0.1-10 microM), but not glibenclamide, induced NO production, significantly increasing it by 1.8-fold (n=6, p<0.05). LY294002 inhibited glimepiride-induced NO production by 68%. Akt was rapidly phosphorylated by glimepiride and antisense oligonucleotides directed to Akt completely inhibited glimepiride-induced NO production. These data demonstrate that glimepiride induces NO production in HCAECs by activating PI3-kinase and Akt, and also suggest that use of glimepiride in type 2 diabetes may show promise for preventing CAD in addition to lowering glucose levels.
authors.affiliation: Department of Internal Medicine, Omiya Medical Center, Jichi Medical School, Amanuma-Cho 1-847, Saitama City 330-8503, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ueba
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kuroki
authors.forename: Shigemasa
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Tomio
authors.initials: T
authors.lastname: Umemoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasu
authors.forename: San-e
authors.initials: SE
authors.lastname: Ishikawa
authors.forename: Muneyasu
authors.initials: M
authors.lastname: Saito
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawakami
mesh_terms: D002478:Cells, Cultured / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: D002867:Chromones; D007004:Hypoglycemic Agents; D009025:Morpholines; D020319:Oligodeoxyribonucleotides, Antisense; D013453:Sulfonylurea Compounds; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C057619:glimepiride; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005905:Glyburide