Document Detail


Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody.
MedLine Citation:
PMID:  15967845     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. METHODS AND RESULTS: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2x) expressed in at least 1 group compared with a common reference (ApoE-/-, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression-dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1alpha, and MIP-1beta. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1alpha located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE-/- mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. CONCLUSIONS: Gene profiling of atherosclerotic plaque progression in ApoE-/- mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.
Authors:
Esther Lutgens; Birgit Faber; Kitty Schapira; Chris T A Evelo; Rachel van Haaften; Sylvia Heeneman; Kitty B J M Cleutjens; Ann Pascale Bijnens; Linda Beckers; J Gordon Porter; Charles R Mackay; Paul Rennert; Veronique Bailly; Matthew Jarpe; Brian Dolinski; Victor Koteliansky; Tony de Fougerolles; Mat J A P Daemen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-06-20
Journal Detail:
Title:  Circulation     Volume:  111     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-28     Completed Date:  2006-02-03     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3443-52     Citation Subset:  AIM; IM    
Affiliation:
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands. e.lutgens@path.unimaas.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / administration & dosage,  pharmacology
Aorta, Thoracic
Apolipoproteins E / deficiency
Atherosclerosis / drug therapy,  genetics*,  pathology
Chemokine CCL2 / immunology
Chemokine CCL8
Chemokines / genetics,  physiology*
Cluster Analysis
Disease Progression
Extracellular Matrix / metabolism
Gene Expression Profiling*
Inflammation / genetics
Male
Mice
Mice, Knockout
Monocyte Chemoattractant Proteins / immunology,  physiology
Peptide Hydrolases / genetics
RNA, Messenger / analysis
Time Factors
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Apolipoproteins E; 0/Ccl2 protein, mouse; 0/Ccl8 protein, mouse; 0/Chemokine CCL2; 0/Chemokine CCL8; 0/Chemokines; 0/Monocyte Chemoattractant Proteins; 0/RNA, Messenger; EC 3.4.-/Peptide Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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