Open AccessTumor Necrosis Factor‐Like Weak Inducer of Apoptosis or Fn14 Deficiency Reduce Elastase Perfusion‐Induced Aortic Abdominal Aneurysm in Mice
Author(s) -
Tarín Carlos,
FernándezLaso Valvanera,
Sastre Cristina,
MadrigalMatute Julio,
Gómez Mónica,
Zaragoza Carlos,
Egido Jesús,
Burkly Linda C.,
MartínVentura Jose L.,
BlancoColio Luis M.
Publication year - 2014
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000723
Subject(s) - medicine , proinflammatory cytokine , angiogenesis , tumor necrosis factor alpha , vascular smooth muscle , elastase , neutrophil elastase , cytokine , inflammation , neovascularization , matrix metalloproteinase , apoptosis , chemokine , cancer research , immunology , endocrinology , biology , smooth muscle , biochemistry , enzyme
Background Abdominal aortic aneurysm ( AAA ) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor‐like weak inducer of apoptosis ( TWEAK ) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown. Methods and Results Experimental AAA with aortic elastase perfusion in mice was induced in wild‐type ( WT ), TWEAK deficient ( TWEAK KO ), or Fn14‐deficient (Fn14 KO ) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD 3 + T cells, neutrophils, CD 31 + microvessels, CCL 2 and CCL 5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells ( VSMC ) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL 5 secretion and MMP ‐9 activation in both VSMC and bone marrow‐derived macrophages, and decrease VSMC viability, effects dependent on Fn14. Conclusions TWEAK /Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix‐degrading protease expression, and vascular remodeling. Blocking TWEAK /Fn14 interaction could be a new target for the treatment of AAA .