S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications

Deepanjana Das, Joseph Gawdzik, Lisa Dellefave-Castillo, Elizabeth M. McNally, Aliya Husain, Jai Raman, Marion A. Hofmann Bowman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The purpose of this study was to determine the relevance of S100A12 expression to human thoracic aortic aneurysms and type A thoracic aortic aneurysm dissection and to study mechanisms of S100A12-mediated dysfunction of aortic smooth muscle cells. Transgenic expression of proinflammatory S100A12 protein in murine aortic smooth muscle causes thoracic aneurysm in genetically modified mice. Immunohistochemistry of aortic tissue (n = 50) for S100A12, myeloperoxidase, and caspase 3 was examined and S100A12-mediated pathways were studied in cultured primary aortic smooth muscle cells. We found S100A12 protein expressed in all cases of acute thoracic aortic aneurysm dissection and in approximately 25% of clinically stable thoracic aortic aneurysm cases. S100A12 tissue expression was associated with increased length of stay in patients undergoing elective surgical repair for thoracic aortic aneurysm, despite similar preoperative risk as determined by European System for Cardiac Operative Risk Evaluation. Reduction of S100A12 expression in human aortic smooth muscle cells using small hairpin RNA attenuates gene and protein expression of many inflammatory- and apoptosis-regulating factors. Moreover, genetic ablation of the receptor for S100A12, receptor for advanced glycation end products (RAGE), in murine aortic smooth muscle cells abolished cytokine-augmented activation of caspase 3 and smooth muscle cell apoptosis in S100A12-expressing cells. S100A12 is enriched in human thoracic aortic aneurysms and dissections. Reduction of S100A12 or genetic ablation of its cell surface receptor, the receptor for advanced glycation end products (RAGE), in aortic smooth muscle resulted in decreased activation of caspase 3 and in reduced apoptosis. By establishing a link between S100A12 expression and apoptosis of aortic smooth muscle cells, this study identifies novel S100A12 signaling pathways and indicates that S100A12 may be a useful molecular marker and possible target for treatment for human aortic diseases.

Original languageEnglish (US)
Pages (from-to)775-785
Number of pages11
JournalJournal of the American College of Cardiology
Volume60
Issue number8
DOIs
StatePublished - Aug 21 2012

Keywords

  • S100 proteins
  • aortic smooth muscle cells
  • cell death
  • receptor for advanced glycation end products
  • thoracic aortic aneurysm and dissection

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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