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(Circulation. 2000;101:1598.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Inhibition of Transplant Vasculopathy in a Rat Aortic Allograft Model After Infusion of Anti-Inflammatory Viral Serpin

Leslie W. Miller, MD; Erbin Dai, MD; Piers Nash, PhD; Liying Liu, MD; Carolyn Icton, BSc; Dennis Klironomos, BSc; Lilly Fan, BSc; Patric N. Nation, DVM; Robert Zhong, MD; Grant McFadden, PhD; Alexandra Lucas, MD

From the Division of Cardiology, University of Minnesota, Minneapolis (L.W.M.); the Cardiovascular Disease Research Group (L.W.M., E.D., L.L., A.L.), the Department of Biochemistry (P.N., G.M.), and the Department of Laboratory Animal Medicine (P.N.N.),University of Alberta, Edmonton, Alberta, Canada; and the Vascular Biology Research Group, Robarts Research Institute (E.D., L.L., C.I., D.K., L.F., G.M., A.L.), the Department of Microbiology and Immunology (P.N., G.M., A.L.), and the Department of Surgery (R.Z.), University of Western Ontario, London, Ontario, Canada.

Correspondence to Alexandra Lucas, MD, John P. Robarts Research Institute, University of Western Ontario, 100 Perth Dr, PO Box 5015, London, Ontario N6A-5K8, Canada. E-mail arl{at}rri.on.ca

Background—Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery.

Methods and Results—Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006).

Conclusions—Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.

Key Words: rejection • transplantation • viruses • serpin • inflammation

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