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J Biol Chem, Vol. 274, Issue 9, 5379-5384, February 26, 1999

Tissue Factor Pathway Inhibitor-2 Is a Novel Mitogen for Vascular Smooth Muscle Cells

Eiji ShinodaDagger , Yoshiki YuiDagger , Ryuichi HattoriDagger , Misaki TanakaDagger , Reiko InoueDagger , Takeshi AoyamaDagger , Yoshihito TakimotoDagger , Youji Mitsui, Kaoru Miyaharaparallel , Yutaka Shizutaparallel , and Shigetake SasayamaDagger

From the Dagger  Third Division, Department of Internal Medicine, Kyoto University Hospital, Shogoin-Kawaracho 54, Kyoto 6068507, Japan, the  National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology, 1-1 Higashi, Tsukuba, Ibaraki 3058566, Japan, and the parallel  Department of Medical Chemistry, Kochi Medical School, Nankoku, Kochi 7838505, Japan

A mitogen for growth-arrested cultured bovine aortic smooth muscle cells was purified to homogeneity from the supernatant of cultured human umbilical vein endothelial cells by heparin affinity chromatography and reverse-phase high performance liquid chromatography. This mitogen was revealed to be tissue factor pathway inhibitor-2 (TFPI-2), which is a Kunitz-type serine protease inhibitor. TFPI-2 was expressed in baby hamster kidney cells using a mammalian expression vector. Recombinant TFPI-2 (rTFPI-2) stimulated DNA synthesis and cell proliferation in a dose-dependent manner (1-500 nM). rTFPI-2 activated mitogen-activated protein kinase (MAPK) activity and stimulated early proto-oncogene c-fos mRNA expression in smooth muscle cells. MAPK, c-fos expression and the mitogenic activity were inhibited by a specific inhibitor of MAPK kinase, PD098059. Thus, the mitogenic function of rTFPI-2 is considered to be mediated through MAPK pathway. TFPI has been reported to exhibit antiproliferative action after vascular smooth muscle injury in addition to the ability to inhibit activation of the extrinsic coagulation cascade. However, structurally similar TFPI-2 was found to have a mitogenic activity for the smooth muscle cell.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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