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203 Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques
  1. Sarah R Langley1,
  2. Karin Willeit2,
  3. Athanasios Didangelos1,
  4. Ljubica Perisic Matic3,
  5. Philipp Skroblin1,
  6. Javier Barallobre-Barreiro1,
  7. Mariette Lengquist3,
  8. Gregor Rungger4,
  9. Alexander Kapustin1,
  10. Ludmilla Kedenko5,
  11. Ruifang Lu1,
  12. Temo Barwari6,
  13. Gonca Suna1,
  14. Xiaoke Yin1,
  15. Bernhard Iglseder7,
  16. Bernhard Paulweber5,
  17. Peter Willeit2,
  18. Joseph Shalhoub8,
  19. Gerard Pasterkamp9,
  20. Claudia Monaco10,
  21. Ulf Hedin3,
  22. Catherine M. Shanahan1,
  23. Johann Willeit2,
  24. Stefan Kiechl Kielch2,
  25. Manuel Mayr1
  1. 1King’s College London
  2. 2Department of Neurology, Medical University Innsbruck
  3. 3Department of Molecular Medicine and Surgery, Vascular Surgery, Karolinksa University
  4. 4Department of Neurology, Bruneck Hospital
  5. 5First Department of Internal Medicine, Paracelsus Medical University
  6. 6King’s college London
  7. 7Department of Geriatric Medicine, Paracelsus Medical University
  8. 8Imperial College
  9. 9University Medical Centre Utrecht
  10. 10Kennedy Institute, University of Oxford

Abstract

Introduction Recent findings have challenged the prevailing histology- or imaging-based definition of the vulnerable plaque.

Methods To investigate molecular characteristics associated with clinical instability of atherosclerosis, we performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from symptomatic versus asymptomatic patients. The proteomics data were integrated with gene expression profiling and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells.

Results The molecular signature of plaques from symptomatic patients identified by proteomics and at least one of the other two approaches comprised matrix metalloproteinase-9, chitinase-3-like protein 1, S100 calcium binding protein A8, S100 calcium binding protein A9, cathepsin B, fibronectin and galectin-3-binding protein. Biomarker candidates were measured in 685 subjects of the Bruneck Study and found to be significantly associated with the progression to advanced atherosclerosis (as assessed by repeated carotid ultrasound) and the incidence of cardiovascular disease over a 10 year follow-up period. A 4-biomarker signature (matrix metalloproteinase-9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction in terms of risk discrimination and classification and was successfully replicated in a second independent population (SAPHIR Study).

Conclusion Our study highlights the strength of tissue-based proteomics for biomarker discovery.

  • Extracellular matrix
  • Atherosclerosis
  • Proteomics and biomarkers

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