Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7345
Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice
J Am Heart Assoc. 2014; 3(4):e000723
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, CD3(+) T cells, neutrophils, CD31(+) microvessels, CCL2 and CCL5 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 CCL5 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.
Animals | Aortic Aneurysm, Abdominal | Apoptosis | Chemokine CCL2 | Chemokine CCL5 | Cytokine TWEAK | Disease Models, Animal | Inflammation | Macrophages | Matrix Metalloproteinase 9 | Mice | Mice, Knockout | Muscle, Smooth, Vascular | Myocytes, Smooth Muscle | Neutrophils | Pancreatic Elastase | Receptors, Tumor Necrosis Factor | T-Lymphocytes | TWEAK Receptor | Tumor Necrosis Factors
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