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J. Biol. Chem., Vol. 278, Issue 20, 18563-18572, May 16, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/20/18563    most recent M209683200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Dai, E. Articles by Lucas, A. Search for Related Content PubMed PubMed Citation Articles by Dai, E. Articles by Lucas, A. Social Bookmarking                      What's this?

Serp-1, a Viral Anti-inflammatory Serpin, Regulates Cellular Serine Proteinase and Serpin Responses to Vascular Injury^*

Erbin Dai, Haiyan Guan, Liying Liu, Stephen Little^§, Grant McFadden^¶, Sepideh Vaziri, Henian Cao, Iordanka A. Ivanova, Leila Bocksch^¶, and Alexandra Lucas^§¶

From the  Vascular Biology Research Group, John P. Robarts' Research Institute, the ^§ Division of Cardiology, London Health Sciences Center, University Hospital, and the ^¶ Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5K8, Canada

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.

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