Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice

Tarín, CarlosFernández-Laso, ValvaneraSastre, CristinaMadrigal-Matute, JulioGómez, MónicaZaragoza, CarlosEgido, JesúsBurkly, Linda CMartín-Ventura, Jose LBlanco-Colio, Luis M2019-03-152019-03-152014-08-04J Am Heart Assoc. 2014; 3(4):e0007232047-9980http://hdl.handle.net/20.500.12105/7345BACKGROUND: 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.engVoRhttp://creativecommons.org/licenses/by-nc/4.0/Fn14MMP activityTWEAKAneurysmInflammationAnimalsAortic Aneurysm, AbdominalApoptosisChemokine CCL2Chemokine CCL5Cytokine TWEAKDisease Models, AnimalInflammationMacrophagesMatrix Metalloproteinase 9MiceMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MuscleNeutrophilsPancreatic ElastaseReceptors, Tumor Necrosis FactorT-LymphocytesTWEAK ReceptorTumor Necrosis FactorsTumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in miceAtribución-NoComercial 4.0 Internacional250927863410.1161/JAHA.113.0007232047-9980Journal of the American Heart Associationopen access