title: Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice.
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.
  
  
  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.
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Tarín
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Valvanera
authors.initials: V
authors.lastname: Fernández-Laso
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Sastre
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Spanish National Cardiovascular Research Center, Madrid, Spain (, C.Z.).
authors.forename: Mónica
authors.initials: M
authors.lastname: Gómez
authors.affiliation: Cardiovascular Joint Research Unit, University Hospital Ramón y Cajal Hospital and University Francisco de Vitoria School of Medicine, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zaragoza
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Biogen Idec, Cambridge, MA (L.C.B.).
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martín-Ventura
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain (C.T., V.F.L., C.S., J.M.M., J.E., J.L.M.V., L.M.B.C.).
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D007249:Inflammation; D008264:Macrophages / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010196:Pancreatic Elastase / Q000633:toxicity; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Fn14; MMP activity; TWEAK; aneurysm; inflammation
references.citation: Stroke. 2006 Aug;37(8):2044-53
references.pmid: 16809572
references.citation: J Biol Chem. 2009 Feb 13;284(7):4439-50
references.pmid: 19074147
references.citation: J Clin Invest. 2007 Nov;117(11):3359-68
references.pmid: 17932568
references.citation: Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):241-5
references.pmid: 14604835
references.citation: Nat Med. 2013 Sep;19(9):1166-72
references.pmid: 23933982
references.citation: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):916-22
references.pmid: 17272745
references.citation: J Clin Invest. 2000 Jun;105(11):1641-9
references.pmid: 10841523
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1259-68
references.pmid: 17395854
references.citation: J Cereb Blood Flow Metab. 2010 Jun;30(6):1147-56
references.pmid: 20068578
references.citation: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2605-13
references.pmid: 16973970
references.citation: Lancet. 2005 Apr 30-May 6;365(9470):1577-89
references.pmid: 15866312
references.citation: Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1452-7
references.pmid: 19574559
references.citation: J Thorac Cardiovasc Surg. 2011 Dec;142(6):1567-74
references.pmid: 21996300
references.citation: Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):718-26
references.pmid: 23288157
references.citation: Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1145-51
references.pmid: 7627708
references.citation: Circ J. 2004 Apr;68(4):396-9
references.pmid: 15056843
references.citation: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2077-82
references.pmid: 16809548
references.citation: Adv Exp Med Biol. 2011;691:305-22
references.pmid: 21153335
references.citation: J Leukoc Biol. 2012 Aug;92(2):265-79
references.pmid: 22672874
references.citation: Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):2061-8
references.pmid: 19778942
references.citation: Cardiovasc Res. 2009 Jun 1;82(3):532-41
references.pmid: 19201759
references.citation: Circulation. 1994 Nov;90(5 Pt 2):II224-7
references.pmid: 7955258
references.citation: Am J Pathol. 2004 Jun;164(6):2077-87
references.pmid: 15161642
references.citation: Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):618-23
references.pmid: 16357310
references.citation: Gastroenterology. 2009 Mar;136(3):912-23
references.pmid: 19109961
references.citation: Cardiovasc Res. 2011 Jan 1;89(1):225-33
references.pmid: 20810696
references.citation: J Biol Chem. 1999 Mar 26;274(13):8455-9
references.pmid: 10085077
references.citation: J Immunol. 2006 Aug 15;177(4):2610-20
references.pmid: 16888023
references.citation: Atherosclerosis. 2011 Feb;214(2):486-9
references.pmid: 21130992
references.citation: Am J Pathol. 1990 Nov;137(5):1199-213
references.pmid: 1700620
references.citation: Biochem Biophys Res Commun. 2002 Dec 6;299(3):488-93
references.pmid: 12445828
references.citation: Nat Rev Drug Discov. 2008 May;7(5):411-25
references.pmid: 18404150
references.citation: Eur J Vasc Endovasc Surg. 1998 Apr;15(4):313-9
references.pmid: 9610343
references.citation: EMBO J. 2006 Dec 13;25(24):5826-39
references.pmid: 17124496
references.citation: Ann N Y Acad Sci. 1996 Nov 18;800:175-85
references.pmid: 8958992
references.citation: Am J Pathol. 1997 Mar;150(3):993-1007
references.pmid: 9060837
references.citation: Eur J Vasc Endovasc Surg. 2009 Jan;37(1):46-55
references.pmid: 19008128