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(Circulation. 1996;94:2890-2900.)
© 1996 American Heart Association, Inc.

Articles

Virus-Encoded Serine Proteinase Inhibitor SERP-1 Inhibits Atherosclerotic Plaque Development After Balloon Angioplasty

Alexandra Lucas, MD; Li-ying Liu, MD; Joanne Macen, PhD; Piers Nash, BSc; Erbin Dai, MD; Michael Stewart, MSc; Kathryn Graham, PhD; Wai Etches, MD; Lynn Boshkov, MD; Patric N. Nation, MD; Dennis Humen, MD; Marita Lundstrom Hobman, PhD; Grant McFadden, PhD

the Division of Cardiology, Department of Medicine (A.L., L.-y.L., E.D., D.H., M.L.H.); the Department of Biochemistry (J.M., P.N., K.G., G.M.); Health Sciences Laboratory Animal Services (P.N.N.); the Department of Laboratory Medicine and Pathology (M.S., W.E., L.B.), University of Alberta, Edmonton, Alberta, Canada.

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

Background Recurrent atherosclerotic plaque growth, restenosis, is a significant clinical problem after interventional procedures. Initiation of restenosis involves activation of inflammatory and thrombotic cascades, which are regulated by serine proteinase enzymes and inhibitors. We have investigated the use of a viral serine proteinase inhibitor, SERP-1, to reduce plaque development after primary balloon angioplasty. This is the first experimental report of the use of a viral anti-inflammatory protein for the prevention of atherosclerosis.

Methods and Results Seventy-four cholesterol-fed rabbits were treated with either local or systemic infusions of SERP-1 protein (or control solutions) after balloon-mediated injury. Sites of SERP-1 infusion in rabbits had dramatically reduced plaque compared with control infusions at the 4-week follow-up. At low-dose infusions (30 to 300 pg), only the primary infusion site had a demonstrable decrease in plaque, whereas at higher-dose infusions (>3000 pg), a generalized reduction in plaque development was detected. An associated decrease in mononuclear cell infiltration of the arterial wall was detected after SERP-1 infusion within the first 24 hours. Infusion of an active-site mutant of SERP-1 (P₁-P₁', ala-ala) lacking serine proteinase inhibitory activity failed to prevent plaque growth.

Conclusions Purified SERP-1, a virus-encoded secreted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine proteinase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine proteinase inhibitors may provide new insight into the regulation of arterial responses to injury.

Key Words: plaque • serpin • angioplasty • immune system

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