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Glimepiride upregulates eNOS activity and inhibits cytokine‐induced NF‐κB activation through a phosphoinoside 3‐kinase–Akt‐dependent pathway
Author(s) -
Jojima T.,
Suzuki K.,
Hirama N.,
Uchida K.,
Hattori Y.
Publication year - 2009
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2008.00923.x
Subject(s) - glimepiride , enos , glibenclamide , wortmannin , protein kinase b , nitric oxide , pharmacology , medicine , ly294002 , endocrinology , umbilical vein , phosphorylation , cytokine , nitric oxide synthase , chemistry , biochemistry , type 2 diabetes , diabetes mellitus , in vitro
Aims: Several studies suggest increased mortality postcoronary angioplasty in patients on sulphonylureas. However, a theoretical reduction in cardiac risk has been suggested with the newer sulphonylurea agents, which differ from the first‐generation agents. In the present study, we investigated whether a third generation of sulphonylurea, glimepiride, might stimulate nitric oxide (NO) production and thereby inhibit cytokine‐induced nuclear factor (NF)‐κB activation in endothelial cells compared with the classical sulphonylurea glibenclamide. Methods and Results: We demonstrated that glimepiride, but not glibenclamide, induces NO production in human umbilical vein endothelial cells (HUVEC). A significant increase in endothelial NO synthase (eNOS) activity, measured in terms of citrulline production, was observed with glimepiride treatment. Akt phosphorylation followed by phosphorylation of eNOS (Ser1177) was observed with glimepiride treatment in HUVEC. Moreover, two phosphoinoside 3‐kinase inhibitors, wortmannin and LY294002, significantly inhibited glimepiride‐induced NO production. We also demonstrated inhibition of tumour necrosis factor‐alpha (TNFα)‐induced NF‐κB activation in HUVEC treated with glimepiride, which was attenuated by pretreatment with N ω ‐nitro‐ l ‐arginine methyl ester. We also demonstrated a marked increase in p65 in nuclear extracts from untreated HUVEC following stimulation with TNFα, which was dose dependently inhibited by glimepiride, but not by glibenclimide in association with NF‐κB levels. Conclusion: These data suggest that glimepiride might be a preferable sulphonylurea agent in the setting of type 2 diabetes and vascular disease because it may have protective effects on vascular endothelial cells.