Localization of tissue factor pathway inhibitor to lipid rafts is not required for inhibition of factor VIIa/tissue factor activity

Dennis J. Dietzen; Garnet G. Jack; Keith L. Page; Tina A. Tetzloff; Connie L. Hall; Alan E. Mast

doi:10.1055/s-0037-1613544

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2003; 89(01): 65-73
DOI: 10.1055/s-0037-1613544

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Localization of tissue factor pathway inhibitor to lipid rafts is not required for inhibition of factor VIIa/tissue factor activity

Dennis J. Dietzen

¹Department of Pediatrics, Washington University, St. Louis, Missouri

,

Garnet G. Jack

³Pathology and Research Services, VA Medical Center, Memphis, Tennessee

,

Keith L. Page

¹Department of Pediatrics, Washington University, St. Louis, Missouri

,

Tina A. Tetzloff

¹Department of Pediatrics, Washington University, St. Louis, Missouri

,

Connie L. Hall

²Pritzker Institute of Medical Engineering, Illinois Institute of Technology, Chicago, Illinois

,

Alan E. Mast

³Pathology and Research Services, VA Medical Center, Memphis, Tennessee

⁴Department of Pathology, University of Tennessee, Memphis, Tennessee, USA

› Institutsangaben

Abstract

Summary

Tissue factor pathway inhibitor (TFPI) abrogates coagulation initiated by the factor VIIa/tissue factor catalytic complex. While the gene structure of TFPI suggests that it is a secreted protein, a large pool of TFPI is associated with the vascular endothelium through its affinity for a glycosylphosphatidylinositol (GPI)-linked membrane protein. Inhibition of tissue factor by TFPI coincides with the translocation of quaternary complexes containing tissue factor, factor VIIa, factor Xa, and TFPI to detergent-insoluble plasma membrane domains rich in cholesterol, sphingomyelin, and GPI-linked proteins known as lipid rafts and caveolae. It is not known if localization of TFPI to these membrane domains is required for its inhibition of tissue factor procoagulant activity. We generated chimeric TFPI molecules linked directly to the plasma membrane via a GPI anchor or hydrophobic transmembrane domain and expressed these in HEK293 cells that produce tissue factor but not endogenous TFPI. The GPI-anchored chimera was exclusively enriched in detergent-insoluble membrane fractions while the transmembrane molecule was not. Transfectants expressing equal levels of the GPI-linked or transmembrane TFPI displayed equal anticoagulant potency as assessed by tissue factor-mediated conversion of factor X to factor Xa. Disruption of lipid rafts with cyclodextrin likewise had no effect on the inhibitory activity of the transmembrane or GPI-linked TFPI chimeras in HEK293 cells, nor on endogenous TFPI expressed by ECV304 cells. Thus, we conclude that the GPI anchor and membrane localization to lipid rafts does not enhance inhibition of factor VIIa/ tissue factor by cell-surface associated TFPI.

Keywords

Tissue factor pathway inhibitor - glycosyl phosphatidylinositol - lipid rafts - coagulation - endothelikum

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References
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