title: High glucose induces plasminogen activator inhibitor-1 expression through Rho/Rho-kinase-mediated NF-kappaB activation in bovine aortic endothelial cells.
abstract: Recently, it has become evident that elevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with myocardial infarction and stroke, especially in patients with diabetes. The molecular mechanisms involved in hyperglycemia-induced PAI-1 expression in bovine aortic endothelial cells (BAEC) were investigated. PAI-1 expression in BAEC was significantly increased in accordance with the concentration of glucose in media from 5.7 mM to 23 mM. Stimulation with high glucose (23 mM) significantly increased small GTPase Rho A activation. Pretreatment with a Rho-kinase inhibitor, Y-27632 (1-10 microM), significantly blocked high glucose-induced PAI-1 expression. NF-kappaB activity determined using the luciferase reporter gene assay was significantly enhanced by high glucose, and pretreatment with Y-27632 inhibited high glucose-induced PAI-1 expression at the basal level. An inhibitor of NF-kappaB action, namely parthenolide (0.1 microM), BAY 11-7082 (5 microM) and SN50 (1 microM), significantly blocked high glucose-mediated PAI-1 expression to a level with low glucose (5.7 mM). These data suggested that high glucose-induced PAI-1 expression in endothelial cells is mediated by NF-kappaB activation through the Rho/Rho-kinase pathway. Inhibition of Rho/Rho-kinase signaling might be a novel target for diabetes and metabolic syndrome.
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Konishi
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Mizutani
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Isaka
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan. Electronic address: mitoka@clin.medic.mie-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003470:Culture Media; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D054460:rho-Associated Kinases