J Pharmacol Exp Ther 2003,
PMID: 14534369
Hamaguchi, Erika; Takamura, Toshinari; Shimizu, Akiko; Nagai, Yukihiro
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)-alpha, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF-alpha-induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF-alpha 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-alpha-induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha-induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha-induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF-alpha-induced PAI-1 secretion, suggesting that both NF-kappaB-dependent and NF-kappaB-independent pathways are involved in TNF-alpha-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-alpha-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-alpha-induced PAI-1 secretion. These results indicate That ERK and NF-kappaB are possible targets of TNF-alpha and troglitazone in the regulation of PAI-1 production.
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Text Mining Data
plasminogen → Tumor necrosis factor-alpha: "
Tumor necrosis factor-alpha and troglitazone
regulate plasminogen activator inhibitor type 1 production through extracellular signal regulated kinase- and nuclear factor-kappaB dependent pathways in cultured human umbilical vein endothelial cells
"
TNF-alpha → PAI-1: "
TNF-alpha induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells ( HUVECs )
"
PAI-1 → TNF-alpha: "
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-alpha induced PAI-1 secretion
"
PAI-1 ⊣ nuclear factor-kappaB (NF-kappaB): "
A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha induced PAI-1 secretion, whereas an inhibitor of extracellular signal regulated kinase ( ERK ) kinase, 2'-amino-3'-methoxyflavone ( PD98059 ), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha induced PAI-1 secretion
"
PAI-1 → TNF-alpha: "
A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha induced PAI-1 secretion, whereas an inhibitor of extracellular signal regulated kinase ( ERK ) kinase, 2'-amino-3'-methoxyflavone ( PD98059 ), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha induced PAI-1 secretion
"
PAI-1 → protein tyrosine kinase: "
A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha induced PAI-1 secretion, whereas an inhibitor of extracellular signal regulated kinase ( ERK ) kinase, 2'-amino-3'-methoxyflavone ( PD98059 ), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha induced PAI-1 secretion
"
PAI-1 → TNF-alpha: "
Together, PD98059 and emodin completely inhibited TNF-alpha induced PAI-1 secretion, suggesting that both NF-kappaB dependent and NF-kappaB independent pathways are involved in TNF-alpha induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK
"
PAI-1 → TNF-alpha: "
Furthermore, we have shown that troglitazone inhibited both TNF-alpha induced PAI-1 protein secretion and mRNA in HUVECs
"
PAI-1 → TNF-alpha: "
Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF-alpha induced PAI-1 secretion
"
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