Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
Circulation Research. 2003
Published online before print August 14, 2003, doi: 10.1161/01.RES.0000090993.01633.D4
A more recent version of this article appeared on September 5, 2003
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
93/5/464    most recent
01.RES.0000090993.01633.D4v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bot, I.
Right arrow Articles by Biessen, E. A.L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bot, I.
Right arrow Articles by Biessen, E. A.L.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Substance via MeSH
Related Collections
Right arrow Other arteriosclerosis
Right arrow Smooth muscle proliferation and differentiation
Right arrow Other Vascular biology

Submitted on December 23, 2002
Revised on August 1, 2003
Accepted on August 1, 2003

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 ; and 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, Germany.

* To whom correspondence should be addressed. 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). {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.
Key words: atherosclerosis • carotid arteries • plaque stability • serpin




This article has been cited by other articles:


Home page
 CirculationHome page
J.-R. Nofer, M. Bot, M. Brodde, P. J. Taylor, P. Salm, V. Brinkmann, T. van Berkel, G. Assmann, and E. A.L. Biessen
FTY720, a Synthetic Sphingosine 1 Phosphate Analogue, Inhibits Development of Atherosclerosis in Low-Density Lipoprotein Receptor Deficient Mice
Circulation, January 30, 2007; 115(4): 501 - 508.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Dai, K. Viswanathan, Y. M. Sun, X. Li, L. Y. Liu, B. Togonu-Bickersteth, J. Richardson, C. Macaulay, P. Nash, P. Turner, et al.
Identification of Myxomaviral Serpin Reactive Site Loop Sequences That Regulate Innate Immune Responses
J. Biol. Chem., March 24, 2006; 281(12): 8041 - 8050.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. M. Knapp, J. E. Ramsey, S.-X. Wang, K. E. Godburn, A. R. Strauch, and R. J. Kelm Jr.
Nucleoprotein Interactions Governing Cell Type-dependent Repression of the Mouse Smooth Muscle {alpha}-Actin Promoter by Single-stranded DNA-binding Proteins Pur{alpha} and Purbeta
J. Biol. Chem., March 24, 2006; 281(12): 7907 - 7918.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. Garcia-Touchard, T. D. Henry, G. Sangiorgi, L. G. Spagnoli, A. Mauriello, C. Conover, and R. S. Schwartz
Extracellular Proteases in Atherosclerosis and Restenosis
Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1119 - 1127.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Lucas and G. McFadden
Secreted Immunomodulatory Viral Proteins as Novel Biotherapeutics
J. Immunol., October 15, 2004; 173(8): 4765 - 4774.
[Abstract] [Full Text] [PDF]


Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.