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(Circulation Research. 2003;93:464.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Serine Protease Inhibitor Serp-1 Strongly Impairs Atherosclerotic Lesion Formation and Induces a Stable Plaque Phenotype in ApoE^-/- Mice

Ilze Bot, Jan H. von der Thüsen, Marjo M.P.C. Donners, Alexandra Lucas, Madelon L. Fekkes, Saskia C.A. de Jager, Johan Kuiper, Mat J.A.P. Daemen, Theo J.C. van Berkel, Sylvia Heeneman, Erik A.L. Biessen

From the Division of Biopharmaceutics (I.B., J.H.v.d.T., M.L.F., S.C.A.d.J., Th.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands; John P. Robarts Research Institute (A.L.), Vascular Biology Research Group, University of Western Ontario, London, Ontario, Canada; and the Department of Pathology (M.M.P.C.D., S.H., M.J.A.P.D.), Cardiovascular Research Institute Maastricht, University of Maastricht, the Netherlands.

Correspondence to Ilze Bot, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, the Netherlands. E-mail i.bot{at}lacdr.leidenuniv.nl

The myxoma virus protein Serp-1 is a member of the serine protease inhibitor superfamily. Serp-1 potently inhibits human serum proteases including plasmin, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA). Serp-1 also displays a high antiinflammatory activity, rendering it a promising candidate for antiatherosclerotic therapy. In this study, we have thus examined the effect of Serp-1 on de novo atherosclerotic plaque formation and on advanced lesions. Perivascular collars were placed around carotid arteries of ApoE^-/- mice to induce atherosclerotic plaques and Serp-1 treatment started at week 1 and week 5 after collar placement. Effects of Serp-1 on de novo atherogenesis were characterized by a significantly lower plaque size than that of control mice (18±5x10³ versus 57±12x10³ µm², respectively; P=0.007). Immunostaining showed a 50% (P=0.004) decrease in the MOMA-2–stained lesion area of Serp-1–treated mice. Treatment of advanced lesions with Serp-1 resulted in a decrease in plaque size and lumen stenosis (P=0.028). -Actin staining of these lesions was significantly increased compared with the control (P=0.017). In both studies, a higher cellularity of the plaque and increased collagen content was observed in Serp-1–treated mice. In vitro studies showed that Serp-1 induces proliferation and migration of vascular smooth muscle cells. In conclusion, Serp-1 inhibits carotid artery plaque growth and progression in ApoE^-/- mice. Equally relevant, it enhances cellularity of the plaque core potentially leading to improved plaque stability. The above results indicate that Serp-1 constitutes a promising lead in antiatherosclerotic therapy.

Key Words: atherosclerosis • carotid arteries • plaque stability • serpin

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