Abstract
NF-kappaB transcription factors regulate the expression of tissue factor (TF), a principal initiator of the coagulation cascade. Dominant among them is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a p50 inhibitor) and genetic deletion of p50 attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. Results of the electrophoretic mobility "supershift" assay and chromatin immunoprecipitation demonstrated the direct interaction of the p50/p65 heterodimer with the NF-kappaB site of the human TF promoter. Andro-treated and p50 null mice both exhibited blunted TF expression and reduced venous thrombosis, which were recapitulated by an anti-murine TF antibody in vivo. Our findings thus indicate that regulation of TF by NF-kappaB transcription factor p50 is essential for the pathogenesis of deep vein thrombosis and suggest that specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and perhaps treating venous thrombosis.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cells, Cultured
-
Diterpenes / pharmacology
-
Diterpenes / therapeutic use
-
Endothelial Cells / metabolism
-
Endothelial Cells / pathology
-
Gene Expression Regulation / drug effects
-
Gene Expression Regulation / genetics
-
Humans
-
Macrophages / metabolism
-
Macrophages / pathology
-
Mice
-
Mice, Mutant Strains
-
Monocytes / metabolism
-
Monocytes / pathology
-
NF-kappa B p50 Subunit / antagonists & inhibitors
-
NF-kappa B p50 Subunit / genetics
-
NF-kappa B p50 Subunit / metabolism*
-
Platelet Aggregation Inhibitors / metabolism*
-
Platelet Aggregation Inhibitors / pharmacology
-
Platelet Aggregation Inhibitors / therapeutic use
-
Thromboplastin / biosynthesis*
-
Venous Thrombosis / genetics
-
Venous Thrombosis / metabolism*
-
Venous Thrombosis / pathology
-
Venous Thrombosis / prevention & control
Substances
-
Diterpenes
-
NF-kappa B p50 Subunit
-
NFKB1 protein, human
-
Platelet Aggregation Inhibitors
-
Nfkb1 protein, mouse
-
andrographolide
-
Thromboplastin