[Inflammation inhibits vascular fibulin-5 expression: Involvement of transcription factor SOX9].
BACKGROUND
Fibulin-5 (FBLN5) is an elastogenic protein critically involved in extracellular matrix (ECM) remodelling, a key process in abdominal aortic aneurysm (AAA). However, the possible contribution of FBLN5 to AAA development has not been addressed.


METHODS
Expression levels were determined by real-time PCR and Western blot in human abdominal aorta from patients with AAA or healthy donors, as well as in human aortic vascular smooth muscle cells (VSMC). Lentiviral transduction, transient transfections, and chromatin immunoprecipitation (ChIP) assays were also performed.


RESULTS
The expression of FBLN5 in human AAA was significantly lower than in healthy donors. FBLN5 mRNA and protein levels and their secretion to the extracellular environment were down-regulated in VSMC exposed to inflammatory stimuli. Interestingly, FBLN5 transcriptional activity was inhibited by TNFα and lipopolysaccharide (LPS), and depends on a SOX response element. In fact, SOX9 expression was reduced in VMSC induced by inflammatory mediators and in human AAA, and correlated with that of FBLN5. Furthermore, SOX9 over-expression limited the reduction of FBLN5 expression induced by cytokines in VSMC. Finally, it was observed that SOX9 interacts with FBLN5 promoter, and that this binding was reduced upon TNFα exposure.


CONCLUSIONS
FBLN5 downregulation in human AAA could contribute to extracellular matrix remodelling induced by the inflammatory component of the disease.
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
Mar
M
Orriols
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
Saray
S
Varona
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
Silvia
S
Aguiló
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
María
M
Galán
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
José
J
Martínez González
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España. Electronic address: crodriguezs@csic-iccc.org.
Cristina
C
Rodríguez
D001011:Aorta / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000473:pathology*; D015153:Blotting, Western; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014409:Tumor Necrosis Factor-alpha
Abdominal aortic aneurysm; Aneurisma de aorta abdominal; Fibulin-5; Fibulina-5; Inflamación; Inflammation; SOX9