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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1804-1811.)
© 1999 American Heart Association, Inc.

Thrombosis

A Transcriptional Repressor of the Tissue Factor Gene in Endothelial Cells

Harry Holzmüller; Thomas Moll; Renate Hofer-Warbinek; Diana Mechtcheriakova; Bernd R. Binder; Erhard Hofer

From the Department of Vascular Biology and Thrombosis Research, Vienna International Research Cooperation Center, University of Vienna, Austria. Present address of T.M., Cardiogene AG, Max-Planck-Strasse 15a, D-40699 Erkrath, Germany.

Correspondence to Erhard Hofer, Department of Vascular Biology and Thrombosis Research, Vienna International Research Cooperation Center, University of Vienna, Brunnerstrasse 59, A-1230 Vienna, Austria. E-mail erhard.hofer{at}univie.ac.at

Abstract—Tissue factor, the high-affinity receptor and cofactor for the plasma serine protease VII/VIIa, is the primary cellular initiator of the blood coagulation cascade. Inside the vasculature, expression of the tissue factor gene must be tightly controlled. Whereas the endothelium normally does not express tissue factor, on stimulation with inflammatory cytokines or endotoxin the gene is transcriptionally upregulated leading to a procoagulant state. We have now detected a repressive cis-acting element in the tissue factor promoter that downmodulates tissue factor transcription in endothelial cells. In reporter gene assays, deletion of this element leads to an increase of tissue factor transcription and insertion of a trimerized site reduces transcription. Specific protein/DNA complexes are formed on the element with nuclear extracts in electrophoretic mobility shift assays and cross-linking of the proteins followed by SDS-PAGE detects the presence of at least 2 subunits of 40 and 60 kDa, respectively. After transfection of different cell types with the reporter genes, the suppressive effect of the element can only be revealed in endothelial cells. These data suggest that this element represents a novel transcription factor target sequence that functions to suppress expression of the tissue factor gene, preferentially in endothelial cells thereby supporting a noncoagulant state.

Key Words: tissue factor • endothelium • transcriptional repressor