High glucose induces plasminogen activator inhibitor-1 expression through Rho/Rho-kinase-mediated NF-kappaB activation in bovine aortic endothelial cells.
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.
Iwasaki
Hitoshi
H
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Okamoto
Ryuji
R
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Kato
Shinya
S
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Konishi
Katsuhisa
K
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Mizutani
Hideo
H
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Yamada
Norikazu
N
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Isaka
Naoki
N
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Nakano
Takeshi
T
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Ito
Masaaki
M
Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan. Electronic address: mitoka@clin.medic.mie-u.ac.jp.
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
D003470:Culture Media; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D054460:rho-Associated Kinases