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



Xing Li1, Heather Schneider1, Andrew Peters1, Colin Macaulay1, Elaine King1, Yunming Sun1, 2, Liying Liu2, 3, Erbin Dai2, 3, Jennifer A Davids3, Grant McFadden2, 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


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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


Abstract

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.