TNF-α mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-κB- and p38 MAPK-dependent

Abstract

Summary. Background: Several proatherothrombotic conditions are associated with enhanced levels of circulating proinflammatory cytokines, which are believed to impair endothelial fibrinolytic capacity. Objective: This study aims at investigating how tumor necrosis factor (TNF)‐α regulates endothelial gene expression of the key fibrinolytic enzyme tissue‐type plasminogen activator (t‐PA). Methods: Cultured human umbilical vein endothelial cells were pretreated with selective inhibitors of the three major inflammatory signaling pathways activated by TNF‐α; the nuclear factor kappa‐B (NF‐κB), the p38 mitogen‐activated protein kinase (p38 MAPK), and the c‐jun N‐terminal kinase (JNK) pathways. Following TNF‐α stimulation, effects on t‐PA gene expression were evaluated with real‐time reverse transcriptase polymerase chain reaction and interactions of nuclear proteins with potential gene regulatory elements were studied with electrophoretic mobility shift assays. Results: Approximately 50% suppression of t‐PA gene expression was observed after prolonged stimulation with TNF‐α (≥24 h). The repression was shown to be preferentially dependent on NF‐κB activation, but also on p38 MAPK signaling. Further, we provide evidence for a TNF‐α induced binding of NF‐κB to the recently described κB site in the t‐PA gene and of cyclic adenosine monophosphate response element binding protein (CREB) to the t‐PA CRE‐like site. Conclusions: We conclude that TNF‐α impairs fibrinolytic capacity in vascular endothelial cells by a NF‐κB and p38 MAPK‐dependent suppression of t‐PA. This mechanism sheds a light on how inflammation contributes to the pathogenesis of cardiovascular diseases.

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