TY - JOUR
T1 - The cd40-traf6 axis is the key regulator of the cd40/cd401 system in neointima formation and arterial remodeling
AU - Donners, Marjo M.P.C.
AU - Beckers, Linda
AU - Lievens, Dirk
AU - Munnix, Imke
AU - Heemskerk, Johan
AU - Janssen, Ben J.
AU - Wijnands, Erwin
AU - Cleutjens, Jack
AU - Zernecke, Alma
AU - Weber, Christian
AU - Ahonen, Cory L.
AU - Benbow, Ulrike
AU - Newby, Andrew C.
AU - Noelle, Randolph J.
AU - Daemen, Mat J.A.P.
AU - Lutgens, Esther
PY - 2008/5/1
Y1 - 2008/5/1
N2 - 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, dueto 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.
AB - 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, dueto 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.
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U2 - 10.1182/blood-2007-05-088906
DO - 10.1182/blood-2007-05-088906
M3 - Article
C2 - 18195092
AN - SCOPUS:47149094263
SN - 0006-4971
VL - 111
SP - 4596
EP - 4604
JO - Blood
JF - Blood
IS - 9
ER -