Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques
File(s)
Published version
Published version
Author(s)
Type
Journal Article
Abstract
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. CONCLUSION: 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. FUNDING: 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.
Date Issued
2017-04-03
Date Acceptance
2017-01-19
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
1546
End Page
1560
Journal / Book Title
Journal of Clinical Investigation
Volume
127
Issue
4
Replaces
10044/1/49259
Copyright Statement
© 2017 Langley et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor
Imperial College Trust
Graham-Dixon Charitable Trust
The Circulation Foundation
Identifier
https://www.jci.org/articles/view/86924
http://www.ncbi.nlm.nih.gov/pubmed/28319050
86924
Grant Number
N/A
DKCC_P09393
Mary Davies F'Ship
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
MYELOID-RELATED PROTEIN-14
SMOOTH-MUSCLE-CELLS
ATHEROSCLEROTIC PLAQUES
CARDIOVASCULAR-DISEASE
INCREASED EXPRESSION
STATISTICAL-MODEL
ARTERY-DISEASE
NATURAL COURSE
PLASMA YKL-40
RISK
Atherosclerosis
Biomarkers
Carotid Artery Diseases
Cells, Cultured
Endarterectomy, Carotid
Extracellular Matrix
Extracellular Matrix Proteins
Female
Humans
Male
Myocytes, Smooth Muscle
Plaque, Atherosclerotic
Proteome
Proteomics
Cells, Cultured
Extracellular Matrix
Myocytes, Smooth Muscle
Humans
Carotid Artery Diseases
Proteome
Extracellular Matrix Proteins
Endarterectomy, Carotid
Proteomics
Female
Male
Atherosclerosis
Plaque, Atherosclerotic
Biomarkers
Immunology
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2017-03-20