Fibrin fragment induction of plasminogen activator inhibitor transcriptionis mediated by activator protein-1 through a highly conserved element

Plasminogen activator inhibitor type-1 (PAI-1), a serine protease inhibitor , affects the processes of fibrinolysis, wound healing, and vascular remode ling. We have demonstrated that PAI-1 transcription is induced by D dimer, a plasmin proteolytic fragment of fibrin, supporting its role in negative f eedback on peri-cellular proteolysis, The focus of this study was to define the mechanism of D dimer's effects on PAI-1 transcription. D dimer increas ed the binding activity of the transcription factor activator protein-1 com ponents c-fos/ junD and c-fos mRNA levels in a time- and concentration-depe ndent manner to a greater extent than fibrinogen, Both basal and D dimer-in duced PAI-1 transcriptional activity were entirely dependent on elements wi thin the -161 to -48 bp region of the PAI-1 gene in fibroblasts. Mutations within the AP-l-like element (-59 to -52 bp) in the PAI-1 gene affected D d imer-induced transcriptional activity, c-fos/junD DNA binding, and basal an d c-fos inducible PAI-1 transcriptional activity. Furthermore, expression o f either wild-type or mutant c-fos proteins augmented or diminished the res ponse of the PAI-1 promoter (-161 to +26 bp) to D dimer, respectively. D di mer-induced binding of c-fos/junD to the highly conserved and unique AP-1 l ike element in the PAI-1 gene provides a mechanism whereby specific fibrin fragments control fibrin persistence at sites of inflammation, fibrosis, an d neoplasia. (C) 1999 by The American Society of Hematology.