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, Lys 254–Met 276, 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.