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

Carlos Tarín, Valvanera Ferńandez-Laso, Cristina Sastre, Julio Madrigal-Matute, Mónica Gómez, Carlos Zaragoza, Jesús Egido, Linda C. Burkly, Jose L. Martín-Ventura, Luis M. Blanco-Colio

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere000723
JournalJournal of the American Heart Association
Volume3
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Aneurysm
  • Fn14
  • Inflammation
  • MMP activity
  • TWEAK

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Tarín, C., Ferńandez-Laso, V., Sastre, C., Madrigal-Matute, J., Gómez, M., Zaragoza, C., Egido, J., Burkly, L. C., Martín-Ventura, J. L., & Blanco-Colio, L. M. (2014). Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice. Journal of the American Heart Association, 3(4), [e000723]. https://doi.org/10.1161/JAHA.113.000723