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Originally published In Press as doi:10.1074/jbc.M006434200 on December 11, 2000

J. Biol. Chem., Vol. 276, Issue 11, 8588-8596, March 16, 2001
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A Truncated Plasminogen Activator Inhibitor-1 Protein Induces and Inhibits Angiostatin (Kringles 1-3), a Plasminogen Cleavage Product*

Mary Jo Mulligan-KehoeDagger , Robert Wagner, Courtney Wieland, and Richard Powell

From the Division of Vascular Surgery, Department of Surgery, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire 03756

Plasminogen activator inhibitor-1 (PAI-1) is a serpin protease inhibitor that binds plasminogen activators (uPA and tPA) at a reactive center loop located at the carboxyl-terminal amino acid residues 320-351. The loop is stretched across the top of the active PAI-1 protein maintaining the molecule in a rigid conformation. In the latent PAI-1 conformation, the reactive center loop is inserted into one of the beta sheets, thus making the reactive center loop unavailable for interaction with the plasminogen activators. We truncated porcine PAI-1 at the amino and carboxyl termini to eliminate the reactive center loop, part of a heparin binding site, and a vitronectin binding site. The region we maintained corresponds to amino acids 80-265 of mature human PAI-1 containing binding sites for vitronectin, heparin (partial), uPA, tPA, fibrin, thrombin, and the helix F region. The interaction of "inactive" PAI-1, rPAI-123, with plasminogen and uPA induces the formation of a proteolytic protein with angiostatin properties. Increasing amounts of rPAI-123 inhibit the proteolytic angiostatin fragment. Endothelial cells exposed to exogenous rPAI-123 exhibit reduced proliferation, reduced tube formation, and 47% apoptotic cells within 48 h. Transfected endothelial cells secreting rPAI-123 have a 30% reduction in proliferation, vastly reduced tube formation, and a 50% reduction in cell migration in the presence of VEGF. These two studies show that rPAI-123 interactions with uPA and plasminogen can inhibit plasmin by two mechanisms. In one mechanism, rPAI-123 cleaves plasmin to form a proteolytic angiostatin-like protein. In a second mechanism, rPAI-123 can bind uPA and/or plasminogen to reduce the number of uPA and plasminogen interactions, hence reducing the amount of plasmin that is produced.

* This work was supported by Research Grant R01-HL59590 from the NHLBI, National Institutes of Health, and by a Pacific Vascular Research Foundation Award.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Surgery, Vascular Surgery, Borwell 530 E, 1 Medical Center Dr., Dartmouth Medical School, Lebanon, NH 03756. Tel.: 603-650-8597; Fax: 603-650-4928; E-mail: mary.j.mulligan-kehoe@dartmouth.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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