title: Serine protease inhibitor Serp-1 strongly impairs atherosclerotic lesion formation and induces a stable plaque phenotype in ApoE-/-mice.
abstract: 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+/-5x10(3) versus 57+/-12x10(3) microm2, 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). Alpha-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.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands. i.bot@lacdr.leidenuniv.nl
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: Marjo M P C
authors.initials: MM
authors.lastname: Donners
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucas
authors.forename: Madelon L
authors.initials: ML
authors.lastname: Fekkes
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015843:Serpins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D014764:Viral Proteins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D015843:Serpins; D014764:Viral Proteins