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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4596-4604. Prepublished online as a Blood First Edition Paper on January 14, 2008; DOI 10.1182/blood-2007-05-088906. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-05-088906v1 111/9/4596    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Donners, M. M. P. C. Articles by Lutgens, E. Search for Related Content PubMed PubMed Citation Articles by Donners, M. M. P. C. Articles by Lutgens, E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling Marjo M. P. C. Donners1,2, Linda Beckers1,2, Dirk Lievens1,2, Imke Munnix1,2, Johan Heemskerk1,2, Ben J. Janssen3, Erwin Wijnands1,2, Jack Cleutjens1,2, Alma Zernecke4, Christian Weber4, Cory L. Ahonen5, Ulrike Benbow6, Andrew C. Newby6, Randolph J. Noelle5, Mat J. A. P. Daemen1,2, and Esther Lutgens1,2 Departments of1 Pathology, 2 Biochemistry, and 3 Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands; 4 Institute for Molecular Cardiovascular Research (IMCAR), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Universitätsklinikum Aachen, Aachen, Germany; 5 Department of Medical Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH; and 6 Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom We investigated the role of CD40 and CD40L in neointima formation and identified the downstream CD40-signaling intermediates (tumor necrosis factor [TNF]–receptor associated factors [TRAF]) involved. Neointima formation was induced in wild-type, CD40–/–, CD40L–/–, and in CD40–/– mice that contained a CD40 transgene with or without mutations at the CD40-TRAF2,3&5, TRAF6, or TRAF2,3,5&6 binding sites. Compared with wild-type mice, CD40–/– mice showed a significant decrease in neointima formation with increased collagen deposition and decreased inflammatory cell infiltration. Neointima formation was also impaired in wild-type mice reconstituted with CD40–/– bone marrow. In vitro, the capacity of CD40–/– leukocytes to adhere to the endothelium was reduced. Ligated carotid arteries of CD40–/– mice showed a smaller total vessel volume and an impaired remodeling capacity, reflected by decreased gelatinolytic/collagenolytic activity. Comparable results were found in mice with defects in CD40-TRAF6 and CD40-TRAF 2/3/5&6 binding, but not in mice with defects in CD40-TRAF2/3&5 binding. Neointima formation and vascular remodeling in CD40-receptor–deficient mice is impaired, due to a decreased inflammatory cell infiltration and matrix-degrading protease activity, with CD40-TRAF6 signaling as the key regulator. This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD40/TRAF6 switch in neointimal hyperplasia Nikolay Malinin and Tatiana Byzova Blood 2008 111: 4424. [Full Text] [PDF]

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