Plasminogen activator inhibitor‐1 inhibits factor VIIa bound to tissue factor |
| |
Authors: | G FLOROVA S IDELL U R PENDURTHI L VIJAYA MOHAN RAO |
| |
Institution: | Center for Biomedical Research and The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, TX, USA |
| |
Abstract: | Summary. Background and objective: A growing body of experimental evidence supports broad inhibitory and regulatory activity of plasminogen activator inhibitor 1 (PAI‐1). The present study was designed to investigate whether PAI‐1 inhibits factor (F) VIIa complexed with tissue factor (TF), a well‐known procoagulant risk factor. Methods and results: The ability of PAI‐1 to inhibit FVIIa‐TF activity was evaluated in both clotting and factor X (FX) activation assays. PAI‐1 and its complex with vitronectin inhibit: (i) clotting activity of FVIIa‐TF (PAI‐1IC50, 817 and 125 nm , respectively); (ii) FVIIa‐TF‐mediated FX activation (PAI‐1IC50, 260 and 50 nm , respectively); and (iii) FVIIa bound to TF expressed on the surface of stimulated endothelial cells (PAI‐1IC50, 260 and 120 nm , respectively). The association rate constant (ka) for PAI‐1 inhibition of FVIIa‐TF was determined using a chromogenic assay. Ka for PAI‐1 inhibition of FVIIa bound to relipidated TF is 3.3‐fold higher than that for FVIIa bound to soluble TF (ka = 0.09 ± 0.01 and 0.027 ± 0.03 μm ?1 min?1, respectively). Vitronectin increases ka for both soluble and relipidated TF by 3.5‐ and 30‐fold, respectively (to 0.094 ± 0.020 and 2.7 ± 0.2 μm ?1 min?1). However, only a 3.5‐ to 5.0‐fold increase in the acylated FVIIa was observed on SDS PAGE in the presence of vitronectin for both relipidated and soluble TF, indicating fast formation of PAI‐1/vitronectin/FVIIa/relipidated TF non‐covalent complex. Conclusions: Our results demonstrate potential anticoagulant activity of PAI‐1 in the presence of vitronectin, which could contribute to regulation of hemostasis under pathological conditions such as severe sepsis, acute lung injury and pleural injury, where PAI‐1 and TF are overexpressed. |
| |
Keywords: | factor VIIa plasminogen activator inhibitor‐1 tissue factor |
|
|