Down-regulation of Fibulin-5 is associated with aortic dilation: role of inflammation and epigenetics

Cardiovasc Res. 2016 Jun 1;110(3):431-42. doi: 10.1093/cvr/cvw082. Epub 2016 Apr 18.


Aims: 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.

Methods and results: 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.

Conclusion: 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.

Keywords: Abdominal aortic aneurysm; Fibulin-5; Histone deacetylases; SOX9; Vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Aorta, Abdominal / metabolism
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / chemically induced
  • Aortic Aneurysm, Abdominal / genetics
  • Aortic Aneurysm, Abdominal / metabolism*
  • Aortic Aneurysm, Abdominal / pathology
  • Binding Sites
  • Case-Control Studies
  • Cells, Cultured
  • Dilatation, Pathologic
  • Disease Models, Animal
  • Down-Regulation
  • Epigenesis, Genetic* / drug effects
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Inflammation Mediators / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Promoter Regions, Genetic
  • RNA Interference
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism


  • Extracellular Matrix Proteins
  • FBLN5 protein, human
  • Fbln5 protein, mouse
  • Histone Deacetylase Inhibitors
  • Inflammation Mediators
  • Recombinant Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Tumor Necrosis Factor-alpha
  • Angiotensin II