Heparin Alters Viral Serpin, Serp-1, Anti-Thrombolytic Activity to Anti-Thrombotic Activity

Li, Xing; Schneider, Heather; Peters, Andrew; Macaulay, Colin; King, Elaine; Sun, Yunming; Liu, Liying; Dai, Erbin; Davids, Jennifer A; McFadden, Grant; Lucas, Alexandra

Heparin Alters Viral Serpin, Serp-1, Anti-Thrombolytic Activity to Anti-Thrombotic Activity

Xing Li¹, Heather Schneider¹, Andrew Peters¹, Colin Macaulay¹, Elaine King¹, Yunming Sun^{1, 2}, Liying Liu^{2, 3}, Erbin Dai^{2, 3}, Jennifer A Davids³, Grant McFadden^{2, 3}, Alexandra Lucas^{*, 2, 3}

¹ Viron Therapeutics Inc., London, Ontario, Canada

² Robarts Research Institute, Division of Cardiology Department of Medicine and Department of Microbiology and Im-munology, University of Western Ontario, London, Ontario, Canada

³ Department of Cardiovascular Medicine and Department of Molecular Genetics and Microbiology, University of Flor-ida, Gainesville, Florida, USA

Article Information

Identifiers and Pagination:

Year: 2008
Volume: 2
First Page: 6
Last Page: 15
Publisher ID: TOBIOCJ-2-6
DOI: 10.2174/1874091X00802010006

Article History:

Received Date: 28/11/2007
Revision Received Date: 8/1/2008
Acceptance Date: 17/1/2008
Electronic publication date: 6/2/2008
Collection year: 2008

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2008 Bentham Science Publishers Ltd.

^* Address correspondence to this author at the Ethel Smith Endowed Chair, Professor, Department of Cardiovascular Medicine, University of Florida, 1600 SW Archer Road, Box 100277, Gainesville, FL 32610-0277. USA; Tel: 1-352-392-0092, 1-352-392-7424; Fax: 1-352-392-6662, E-mail: alexandra.lucas@medicine.ufl.edu

Serine protease inhibitors (serpins) regulate coagulation and inflammation. Heparin, a glycosaminoglycan, is an important cofactor for modulation of the inhibitory function of mammalian serpins. The secreted myxoma viral serpin, Serp-1 exerts profound anti-inflammatory activity in a wide range of animal models. Serp-1 anti-inflammatory and anti-atherogenic activity is dependent upon inhibition of the uPA / uPA receptor thrombolytic complex. We demonstrate here that heparin binds to Serp-1 and enhances Serp-1 inhibition of thrombin, a human pro-thrombotic serine protease, in vitro, altering inhibitory activity to a more predominant anti-thrombotic activity. Heparin also facilitates the simultaneous thrombin-mediated cleavage of Serp-1 and prevents formation of a serpin-typical SDS-resistant complex, implying mutual neutralization of Serp-1 and thrombin. In a cell-based assay, heparin facilitates Serp-1 reversal of cellular activation by stabilizing cellular membrane fluidity in thrombin-activated monocytes. In conclusion, heparin and other GAGs serve as cofactors enhancing Serp-1 regulation of local thrombotic and inflammatory pathways

Keywords: Serpin, heparin, myxoma virus, thrombosis, GAGs, thrombin.

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RESEARCH ARTICLE

Heparin Alters Viral Serpin, Serp-1, Anti-Thrombolytic Activity to Anti-Thrombotic Activity

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