The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling

被引：75

作者：

Donners, Marjo M. P. C. ^{[1
,2
]}

Beckers, Linda ^{[1
,2
]}

Lievens, Dirk ^{[1
,2
]}

Munnix, Imke ^{[1
,2
]}

Heemskerk, Johan ^{[1
,2
]}

Janssen, Ben J. ^{[3
]}

Wijnands, Erwin ^{[1
,2
]}

Cleutjens, Jack ^{[1
,2
]}

Zernecke, Alma ^{[4
]}

Weber, Christian ^{[4
]}

Ahonen, Cory L. ^{[5
]}

Benbow, Ulrike ^{[6
]}

Newby, Andrew C. ^{[6
]}

Noelle, Randolph J. ^{[5
]}

Daemen, Mat J. A. P. ^{[1
,2
]}

Lutgens, Esther ^{[1
,2
]}

机构：

[1] Univ Maastricht, Cardiovasc Res Inst Maastricht, Dept Pathol, NL-6200 MD Maastricht, Netherlands

[2] Univ Maastricht, Cardiovasc Res Inst Maastricht, Dept Biochem, NL-6200 MD Maastricht, Netherlands

[3] Univ Maastricht, Cardiovasc Res Inst Maastricht, Dept Pharmacol & Toxicol, NL-6200 MD Maastricht, Netherlands

[4] Univ Aachen, Univ Klinikum Aachen, Rhein Westfal TH Aachen, IMCAR, D-5100 Aachen, Germany

[5] Dartmouth Med Sch, Dept Med Microbiol & Immunol, Lebanon, NH USA

[6] Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Bristol, Avon, England

来源：

BLOOD | 2008年 / 111卷 / 09期

关键词：

D O I：

10.1182/blood-2007-05-088906

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：4596 / 4604

页数：9

共 27 条

[1] The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells [J].