Two receptor systems are involved in the plasma clearance of tissue factor pathway inhibitor in vivo

M. Narita, G. Bu, G. M. Olins, D. A. Higuchi, J. Herz, G. J. Broze, A. L. Schwartz

Research output: Contribution to journalArticle

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Abstract

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the blood coagulation factor VIIa-tissue factor complex, as well as a direct inhibitor of factor Xa. Intravenously administered TFPI is rapidly cleared from circulation predominantly via liver. We previously reported that the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic receptor, mediates the uptake and degradation of TFPI in hepatoma cells. This process is inhibited by a 39-kDa receptor-associated protein which binds to LRP and regulates its ligand binding activity. However, a distinct, low affinity binding site (perhaps heparin sulfate proteoglycans, HSPGs) on the endothelium and liver is thought to be responsible for the majority of TFPI cell surface binding. In the current study, we investigated the role of LRP and this second binding site in the clearance of 125I- TFPI in vivo using competitors and inhibitors of the receptors. Mice overexpressing the 39-kDa protein via adenoviral-mediated gene transfer displayed diminished plasma clearance of 125I-TFPI. Blockade of cell surface HSPGs sites by incubation with the positively charged molecule, protamine, inhibited 125I-TFPI binding to the hepatoma cells in vitro. In addition, preadministration of protamine in vivo prolonged the plasma clearance of 125I-TFPI in a dose-dependent manner. However, a dramatic increase of the plasma half-life of 125I-TFPI and virtual elimination of 125I-TFPI clearance was observed in mice overexpressing the 39-kDa protein and administered protamine. Taken together, our results suggest that two receptor mechanisms are involved in the clearance of TFPI in vivo.

Original languageEnglish (US)
Pages (from-to)24800-24804
Number of pages5
JournalJournal of Biological Chemistry
Volume270
Issue number42
DOIs
StatePublished - 1995

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Plasmas
Protamines
Lipoprotein Receptors
Proteins
Liver
LDL-Receptor Related Protein-Associated Protein
Hepatocellular Carcinoma
lipoprotein-associated coagulation inhibitor
Binding Sites
LDL-Receptor Related Proteins
Gene transfer
Factor VIIa
LDL Receptors
Thromboplastin
Blood Coagulation
Protein Binding
Endothelium
Half-Life
Blood
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Two receptor systems are involved in the plasma clearance of tissue factor pathway inhibitor in vivo. / Narita, M.; Bu, G.; Olins, G. M.; Higuchi, D. A.; Herz, J.; Broze, G. J.; Schwartz, A. L.

In: Journal of Biological Chemistry, Vol. 270, No. 42, 1995, p. 24800-24804.

Research output: Contribution to journalArticle

Narita, M. ; Bu, G. ; Olins, G. M. ; Higuchi, D. A. ; Herz, J. ; Broze, G. J. ; Schwartz, A. L. / Two receptor systems are involved in the plasma clearance of tissue factor pathway inhibitor in vivo. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 42. pp. 24800-24804.
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