Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques.
BACKGROUND
The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology- and imaging-based definitions of the "vulnerable plaque," necessitating an improved approach for predicting onset of symptoms.


METHODS
We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies.


RESULTS
Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and 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 and was successfully replicated in an independent cohort, the SAPHIR study.


CONCLUSIONS
The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery.


BACKGROUND
UK: British Heart Foundation (BHF); King's BHF Center; and the National Institute for Health Research Biomedical Research Center based at Guy's and St Thomas' NHS Foundation Trust and King's College London in partnership with King's College Hospital. Austria: Federal Ministry for Transport, Innovation and Technology (BMVIT); Federal Ministry of Science, Research and Economy (BMWFW); Wirtschaftsagentur Wien; and Standortagentur Tirol.
Sarah R
SR
Langley
Karin
K
Willeit
Athanasios
A
Didangelos
Ljubica Perisic
LP
Matic
Philipp
P
Skroblin
Javier
J
Barallobre-Barreiro
Mariette
M
Lengquist
Gregor
G
Rungger
Alexander
A
Kapustin
Ludmilla
L
Kedenko
Chris
C
Molenaar
Ruifang
R
Lu
Temo
T
Barwari
Gonca
G
Suna
Xiaoke
X
Yin
Bernhard
B
Iglseder
Bernhard
B
Paulweber
Peter
P
Willeit
Joseph
J
Shalhoub
Gerard
G
Pasterkamp
Alun H
AH
Davies
Claudia
C
Monaco
Ulf
U
Hedin
Catherine M
CM
Shanahan
Johann
J
Willeit
Stefan
S
Kiechl
Manuel
M
Mayr
D050197:Atherosclerosis / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000601:surgery; D002478:Cells, Cultured; D016894:Endarterectomy, Carotid; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics
D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D020543:Proteome