Human recombinant tissue-factor pathway inhibitor prevents the proliferation of cultured human neonatal aortic smooth muscle cells.
Tissue-factor pathway inhibitor (TFPI) inhibits the procoagulant activity of the tissue-factor/factor VIIa complex. It was recently reported that TFPI prevented restenosis following tissue injury in a rabbit atherosclerotic model. In order to clarify the mechanism behind this successful prevention of restenosis, we investigated the direct effect of human recombinant TFPI (h-rTFPI) on the proliferation of cultured human neonatal aortic smooth muscle cells (hSMC). We found that h-rTFPI exhibits inhibitory activity toward hSMC proliferation, while h-rTFPI-C which lacks the carboxyl (C)-terminal region does not. Furthermore, we found that h-rTFPI binds to hSMCs with K(d) = 526 nM but that this binding is inhibited by the addition of the synthetic C-terminal peptide, Lys254-Met276, to h-rTFPI. Thus, the interaction of h-rTFPI with hSMCs mediated via the C-terminal region is responsible for the anti-proliferative action of h-rTFPI. On the basis of these results, we presume that the anti-proliferative effect of h-rTFPI in addition to its anticoagulant function plays a significant role in preventing restenosis following tissue injury.
Kamikubo
Y
Y
The Chemo-Sero-Therapeutic Research Institute, Kumamoto City, Japan. VYG07346@niftyserve.or.jp
Nakahara
Y
Y
Takemoto
S
S
Hamuro
T
T
Miyamoto
S
S
Funatsu
A
A
D000595:Amino Acid Sequence; D001011:Aorta / Q000166:cytology; D001024:Aortic Valve Stenosis / Q000517:prevention & control; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D008074:Lipoproteins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D008074:Lipoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D013925:Thromboplastin