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

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Abstract
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)-α, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF-α-induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF-α 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-α-induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-α-induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2′-amino-3′-methoxyflavone (PD98059), and a nuclear factor-κB (NF-κB) inhibitor, emodin, partly inhibited TNF-α-induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF-α-induced PAI-1 secretion, suggesting that both NF-κB-dependent and NF-κB-independent pathways are involved in TNF-α-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-α-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-α-induced PAI-1 secretion. These results indicate That ERK and NF-κB are possible targets of TNF-α and troglitazone in the regulation of PAI-1 production.