Modification of the secretion pattern of proteases, inflammatory mediators, and extracellular matrix proteins by human aortic valve is key in severe aortic stenosis

Gloria Alvarez-Llamas, Tatiana Martín-Rojas, Fernando de la Cuesta, Enrique Calvo, Felix Gil-Dones, Veronica M Dardé, Luis F Lopez-Almodovar, Luis R Padial, Juan-Antonio Lopez, Fernando Vivanco, Maria G Barderas

Research output: Contribution to journalArticlepeer-review

Abstract

One of the major challenges in cardiovascular medicine is to identify candidate biomarker proteins. Secretome analysis is particularly relevant in this search as it focuses on a subset of proteins released by a cell or tissue under certain conditions. The sample can be considered as a plasma subproteome and it provides a more direct approximation to the in vivo situation. Degenerative aortic stenosis is the most common worldwide cause of valve replacement. Using a proteomic analysis of the secretome from aortic stenosis valves we could identify candidate markers related to this pathology, which may facilitate early diagnosis and treatment. For this purpose, we have designed a method to validate the origin of secreted proteins, demonstrating their synthesis and release by the tissue and ruling out blood origin. The nLC-MS/MS analysis showed the labeling of 61 proteins, 82% of which incorporated the label in only one group. Western blot and selective reaction monitoring differential analysis, revealed a notable role of the extracellular matrix. Variation in particular proteins such as PEDF, cystatin and clusterin emphasizes the link between aortic stenosis and atherosclerosis. In particular, certain proteins variation in secretome levels correlates well, not only with label incorporation trend (only labeled in aortic stenosis group) but, more importantly, with alterations found in plasma from an independent cohort of samples, pointing to specific candidate markers to follow up in diagnosis, prognosis, and therapeutic intervention.

Original languageEnglish
Pages (from-to)2426-2439
Number of pages14
JournalMolecular and Cellular Proteomics
Volume12
Issue number9
Early online date23 May 2013
DOIs
Publication statusPublished - 1 Sep 2013

Keywords

  • Aged
  • Aortic Valve
  • Aortic Valve Stenosis
  • Blotting, Western
  • Extracellular Matrix Proteins
  • Female
  • Humans
  • Inflammation Mediators
  • Isotope Labeling
  • Male
  • Mass Spectrometry
  • Peptide Hydrolases
  • Protein Interaction Maps
  • Proteome
  • Proteomics
  • Reproducibility of Results
  • Time Factors

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