Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques

Sarah R. Langley, Karin Willeit, Athanasios Didangelos, Ljubica Perisic Matic, Philipp Skroblin, Javier Barallobre-Barreiro, Mariette Lengquist, Gregor Rungger, Alexander Kapustin, Ludmilla Kedenko, Chris Molenaar, Ruifang Lu (+15 others)
2017 Journal of Clinical Investigation  
BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histologyand 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
more » ... 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-3binding protein) improved [...] Clinical Medicine Vascular biology Find the latest version: Atherosclerosis is a chronic and progressive disease of the arterial wall and the main underlying cause of stroke, myocardial infarction (MI), and cardiac death (1, 2). The evolution of atherosclerotic plaques involves endothelial dysfunction, accumulation of lipids and inflammatory cells, as well as remodeling of the extracellular matrix (ECM). Previously, atherosclerotic plaques were defined by histological appearance. Plaques with thin fibrous caps and a large lipid pool were classified as "vulnerable lesions." Lipid-poor plaques rich in ECM with thick fibrous caps were considered "stable." Recent findings have challenged this "vulnerable plaque" concept (3, 4): First, intravascular imaging revealed that only a small percentage of thin-capped plaques cause clinical events (4, 5). Second, shifts in risk factor profiles (e.g., smoking cessation) and widespread use of statins are associated with a change in histopathological appearance of atherosclerotic lesions: "vulnerable plaques" with large lipid pools are far less common (3). Instead, superficial plaque erosions may trigger more cardiovascular events (3, 4) . 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-3binding 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.
doi:10.1172/jci86924 pmid:28319050 pmcid:PMC5373893 fatcat:grp7pg66nbdzjdsyc6jrm7w544