S100A12 mediates aortic wall remodeling and aortic aneurysm

Marion Hofmann Bowman, Jeannine Wilk, Ahlke Heydemann, Gene Kim, Jalees Rehman, Joseph A. Lodato, Jai Raman, Elizabeth M. McNally

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

RATIONALE: S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear. OBJECTIVE: To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22α promoter because S100A12 is not present in mice. METHODS AND RESULTS: Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor β pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells. CONCLUSIONS: S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.

Original languageEnglish (US)
Pages (from-to)145-154
Number of pages10
JournalCirculation research
Volume106
Issue number1
DOIs
StatePublished - 2010

Keywords

  • Aortic aneurysms
  • Calgranulins
  • RAGE
  • S100A12
  • Smooth muscle cell differentiation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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