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J. Biol. Chem., Vol. 281, Issue 12, 8175-8182, March 24, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/12/8175    most recent M509182200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zheng, P.-S. Articles by Yang, B. B. Search for Related Content PubMed PubMed Citation Articles by Zheng, P.-S. Articles by Yang, B. B. Social Bookmarking                      What's this?

Versican G3 Domain Promotes Blood Coagulation through Suppressing the Activity of Tissue Factor Pathway Inhibitor-1^*

Peng-Sheng Zheng, Marciano Reis, Cathy Sparling, Daniel Y. Lee, David P. La Pierre, Chung-Kwun Amy Wong, Zhaoqun Deng, Shireen Kahai, Jianping Wen, and Burton B. Yang¹

From the Sunnybrook & Women's College Health Sciences Centre and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M4N 3M5, Canada

We have detected versican, a member of the large chondroitin sulfate proteoglycans, and its degraded C-terminal G3 fragments in human plasma and observed that the versican G3 domain promoted blood coagulation. Silencing G3 expression with small interfering RNA reduced the effect of G3 on coagulation. Plasma coagulation assays suggest that G3 enhances coagulation irrespective of its actions on platelets and white blood cells. To examine how versican affected blood coagulation, we used normal human plasma and different types of coagulation factor-deficient plasmas. The experiments indicated that versican enhanced coagulation through the extrinsic pathway, and that Factor VII was the target molecule. FVII activity assays showed that G3 activated FVII in the presence of plasma but not with purified FVII directly. Yeast two-hybrid, immunoprecipitation, and gel co-migration assays showed that G3 interacted with the tissue factor pathway inhibitor-1 (TFPI-1). TFPI-1 activity assays suggested that G3 inhibited TFPI-1 activity, allowing FVIIa and FXa to facilitate the coagulation process. G3-induced blood coagulation was further confirmed with a mouse model in a real-time manner. Taken together, these results indicate that versican may represent a new target for the development of therapies against atherosclerosis.

Received for publication, August 19, 2005 , and in revised form, January 10, 2006.

^* This work was supported by Grant MOP-74469 from the Canadian Institutes of Health Research (to B. B. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Research Bldg., 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. Tel.: 416-480-5874; Fax: 416-480-5737; E-mail: burton.yang{at}sw.ca.

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