title: Down-regulation of Fibulin-5 is associated with aortic dilation: role of inflammation and epigenetics.
abstract: Destructive remodelling of extracellular matrix (ECM) and inflammation lead to dilation and ultimately abdominal aortic aneurysm (AAA). Fibulin-5 (FBLN5) mediates cell-ECM interactions and elastic fibre assembly and is critical for ECM remodelling. We aimed to characterize FBLN5 regulation in human AAA and analyse the underlying mechanisms.
  
  
  
  FBLN5 expression was significantly decreased in human aneurysmatic aortas compared with healthy vessels. Local FBLN5 knockdown promoted aortic dilation and enhanced vascular expression of inflammatory markers in Ang II-infused C57BL/6J mice. Inflammatory stimuli down-regulated FBLN5 expression and transcriptional activity in human aortic vascular smooth muscle cells (VSMC). Further, aortic FBLN5 expression was reduced in LPS-challenged mice. A SOX response element was critical for FBLN5 promoter activity. The SOX9 expression pattern in human AAA parallels that of FBLN5, and like FBLN5, it was reduced in TNFα-stimulated VSMC. Interestingly, SOX9 over-expression prevented the cytokine-mediated reduction of FBLN5 expression and transcription. The inhibition of Class I histone deacetylases (HDACs) by MS-275 or gene silencing attenuated the inflammation-mediated decrease of FBLN5 expression in VSMC and in the vascular wall. Consistently, HDAC inhibition counteracted the reduction of SOX9 expression induced by inflammatory stimuli and prevented the TNFα-mediated decrease in the binding of SOX9 to FBLN5 promoter normalizing FBLN5 expression.
  
  
  
  We evidence the deregulation of FBLN5 in human AAA and identify a SOX9/HDAC-dependent mechanism involved in the down-regulation of FBLN5 by inflammation. HDAC inhibitors or pharmacological approaches that aimed to preserve FBLN5 could be useful to prevent the disorganization of ECM induced by inflammation in AAA.
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Orriols
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Saray
authors.initials: S
authors.lastname: Varona
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Martí-Pàmies
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Guadall
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, Barcelona, Spain.
authors.forename: José Román
authors.initials: JR
authors.lastname: Escudero
authors.affiliation: IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camacho
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Vila
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain crodriguezs@csic-iccc.org jmartinez@csic-iccc.org.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón N° 11), Avda. Sant Antoni Maria Claret 167, 08025, IIB-Sant Pau, Barcelona, Spain crodriguezs@csic-iccc.org jmartinez@csic-iccc.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C120769:Fbln5 protein, mouse; D056572:Histone Deacetylase Inhibitors; D018836:Inflammation Mediators; D011994:Recombinant Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II
keywords: Abdominal aortic aneurysm; Fibulin-5; Histone deacetylases; SOX9; Vascular smooth muscle cells