title: Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury.
abstract: Complex DNA viruses have tapped into cellular serpin responses that act as key regulatory steps in coagulation and inflammatory cascades. Serp-1 is one such viral serpin that effectively protects virus-infected tissues from host inflammatory responses. When given as purified protein, Serp-1 markedly inhibits vascular monocyte invasion and plaque growth in animal models. We have investigated mechanisms of viral serpin inhibition of vascular inflammatory responses. In vascular injury models, Serp-1 altered early cellular plasminogen activator (tissue plasminogen activator), inhibitor (PAI-1), and receptor (urokinase-type plasminogen activator) expression (p < 0.01). Serp-1, but not a reactive center loop mutant, up-regulated PAI-1 serpin expression in human endothelial cells. Treatment of endothelial cells with antibody to urokinase-type plasminogen activator and vitronectin blocked Serp-1-induced changes. Significantly, Serp-1 blocked intimal hyperplasia (p < 0.0001) after aortic allograft transplant (p < 0.0001) in PAI-1-deficient mice. Serp-1 also blocked plaque growth after aortic isograft transplant and after wire-induced injury (p < 0.05) in PAI-1-deficient mice indicating that increase in PAI-1 expression is not required for Serp-1 to block vasculopathy development. Serp-1 did not inhibit plaque growth in uPAR-deficient mice after aortic allograft transplant. We conclude that the poxviral serpin, Serp-1, attenuates vascular inflammatory responses to injury through a pathway mediated by native uPA receptors and vitronectin.
authors.affiliation: Vascular Biology Research Group, John P. Robarts' Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.
authors.forename: Erbin
authors.initials: E
authors.lastname: Dai
authors.forename: Haiyan
authors.initials: H
authors.lastname: Guan
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Stephen
authors.initials: S
authors.lastname: Little
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Sepideh
authors.initials: S
authors.lastname: Vaziri
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Iordanka A
authors.initials: IA
authors.lastname: Ivanova
authors.forename: Leila
authors.initials: L
authors.lastname: Bocksch
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucas
mesh_terms: D017130:Angioplasty; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism* / Q000502:physiology*; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: D015843:Serpins; D014764:Viral Proteins; D012697:Serine Endopeptidases; D014568:Urokinase-Type Plasminogen Activator