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CELLULAR AND MOLECULAR

Tumor Necrosis Factor- and Troglitazone Regulate Plasminogen Activator Inhibitor Type 1 Production through Extracellular Signal-Regulated Kinase- and Nuclear Factor-B-Dependent Pathways in Cultured Human Umbilical Vein Endothelial Cells

Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan

Plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherosclerosis in diabetic patients. PAI-1 is produced by endothelial cells stimulated with various inflammatory cytokines, such as tumor necrosis factor (TNF)-, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF--induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF- induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells (HUVECs). A specific inhibitor for p38 mitogen-activated protein kinase, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580), and a protein kinase C inhibitor, calphostin C, had no inhibitory effects on TNF--induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF--induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-B (NF-B) inhibitor, emodin, partly inhibited TNF--induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF--induced PAI-1 secretion, suggesting that both NF-B-dependent and NF-B-independent pathways are involved in TNF--induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK. Furthermore, we have shown that troglitazone inhibited both TNF--induced PAI-1 protein secretion and mRNA in HUVECs. Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF--induced PAI-1 secretion. These results indicate That ERK and NF-B are possible targets of TNF- and troglitazone in the regulation of PAI-1 production.

Address correspondence to: Dr. Toshinari Takamura, Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: tt{at}medf.m.kanazawa-u.ac.jp

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