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Extracellular Matrix Proteomics Identifies Molecular Signature of Symptomatic Carotid Plaques

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Extracellular Matrix Proteomics Identifies Molecular Signature of Symptomatic Carotid Plaques CLINICAL MEDICINE The Journal of Clinical Investigation Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques Sarah R. Langley,1,2 Karin Willeit,3 Athanasios Didangelos,1 Ljubica Perisic Matic,4 Philipp Skroblin,1 Javier Barallobre-Barreiro,1 Mariette Lengquist,4 Gregor Rungger,5 Alexander Kapustin,1 Ludmilla Kedenko,6 Chris Molenaar,1,7 Ruifang Lu,1 Temo Barwari,1 Gonca Suna,1 Xiaoke Yin,1 Bernhard Iglseder,8 Bernhard Paulweber,6 Peter Willeit,3,9 Joseph Shalhoub,10 Gerard Pasterkamp,11 Alun H. Davies,10 Claudia Monaco,12 Ulf Hedin,4 Catherine M. Shanahan,1 Johann Willeit,3 Stefan Kiechl,3 and Manuel Mayr1 1King’s British Heart Foundation Centre, King’s College London, London, United Kingdom. 2Duke-NUS Medical School, Singapore. 3Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 4Department of Molecular Medicine and Surgery, Vascular Surgery, Karolinska Institute, Stockholm, Sweden. 5Department of Neurology, Bruneck Hospital, Bruneck, Italy. 6First Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria. 7Nikon Imaging Centre, King’s College London, London, United Kingdom. 8Department of Geriatric Medicine, Paracelsus Medical University, Salzburg, Austria. 9Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 10Department of Surgery and Cancer, Imperial College London, London, United Kingdom. 11Laboratory of Clinical Chemistry and Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 12Kennedy Institute, University of Oxford, Oxford, United Kingdom 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. Introduction plaques involves endothelial dysfunction, accumulation of lipids Atherosclerosis is a chronic and progressive disease of the arterial and inflammatory cells, as well as remodeling of the extracellular wall and the main underlying cause of stroke, myocardial infarc- matrix (ECM). Previously, atherosclerotic plaques were defined tion (MI), and cardiac death (1, 2). The evolution of atherosclerotic 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 “sta- Authorship note: S.R. Langley, K. Willeit, and A. Didangelos contributed equally to this work. ble.” Recent findings have challenged this “vulnerable plaque” con- Conflict of interest: P. Willeit, J. Willeit, S. Kiechl, or M. Mayr are named inventors on unrelated patents (EP15193448.6; EP2430453 B1, US8546089, EP2576826B, JP2013- cept (3, 4): First, intravascular imaging revealed that only a small 513740; EP2776580 B1, DE112013006129T5, GB2524692A; EP3004889 A1; EP3004885 A1, percentage of thin-capped plaques cause clinical events (4, 5). Sec- US2016/0123994). ond, shifts in risk factor profiles (e.g., smoking cessation) and wide- License: This work is licensed under the Creative Commons Attribution 4.0 International spread use of statins are associated with a change in histopathologi- License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. cal appearance of atherosclerotic lesions: “vulnerable plaques” with Submitted: February 23, 2016; Accepted: January 19, 2017. Reference information: J Clin Invest. 2017;127(4):1546–1560. large lipid pools are far less common (3). Instead, superficial plaque https://doi.org/10.1172/JCI86924. erosions may trigger more cardiovascular events (3, 4). 1546 jci.org Volume 127 Number 4 April 2017 The Journal of Clinical Investigation CLINICAL MEDICINE Figure 1. ECM proteomics of carotid endarterectomies. Volcano plots of differences in abundance in (A) the proteome of the NaCl fraction (n = 12) and (B) the proteome of the GuHCl fraction (n = 12) between symptomatic and asymptomatic patients. Colors represent FDR levels (red, FDR <1%; orange, FDR <5%; green, FDR <10%; blue, FDR ≥10%, by NSAF-PLGEM; FC, fold change), and the labeled dots are those that were significantly differentially expressed between the plaques from symptomatic and asymptomatic patients (FDR <10%). (C) Coexpression network in the NaCl fraction (n = 12) calculated from Pearson cor- relations with edges defined at FDR <20% (Q values). The sizes of the nodes indicate the level of confidence for the differential expression between plaques from symptomatic and asymptomatic patients, and the colors represent different protein classifications (yellow, growth factors, cytokines, and regulatory factors; green, apolipoproteins; pink, collagens; orange, proteases/peptidases and inhibitors; blue, matricellular proteins and glycoproteins; white, other). Since histological appearance alone is insufficient to predict specimens and secretome analysis of lipid-loaded human vascular symptomatic disease, new approaches are needed to define the smooth muscle cells (SMCs). The proteomics data were integrated biological features of atherosclerotic lesions responsible for car- with plaque transcriptomic data from the Biobank of Karolinska diovascular syndromes and to test whether such features could Endarterectomies (BiKE) (11). The final selection of candidate be of clinical value in predicting events (4). Markers of systemic biomarkers and a 4-biomarker signature derived from the indi- inflammation such as C-reactive protein (CRP) are elevated in vidual components was validated in the community-based Bru- subjects at risk for cardiovascular disease (CVD) but lack the spec- neck study, which is unique in its long-term follow-up and detailed ificity required for reliable differentiation between lesions from monitoring of atherosclerosis manifestation and progression, and symptomatic and asymptomatic patients (6). Recent advances in in a second independent cohort (Salzburg Atherosclerosis Preven- elucidating molecular processes involved in plaque destabilization tion program in subjects at High Individual Risk [SAPHIR] study). have highlighted the importance of the vascular ECM and its asso- ciated proteins (7, 8). We have previously developed a proteomics Results methodology allowing a detailed analysis of the vascular ECM and Proteomics of the ECM of carotid endarterectomies. We applied our associated proteins in the extracellular space (9, 10). published three-step extraction methodology (9, 10) to analyze The aim of the present study was to identify a protein signa- ECM and ECM-associated proteins of carotid endarterectomy ture for symptomatic plaques by applying a tissue- and cell-based specimens previously analyzed by lipidomics (12). Six were from proteomics discovery approach involving carotid endarterectomy symptomatic and 6 from asymptomatic patients, with equal age jci.org Volume 127 Number 4 April 2017 1547 CLINICAL MEDICINE The Journal of Clinical Investigation each group, we found 110 ECM or ECM- Table 1. Proteins differentially expressed between symptomatic and asymptomatic plaques associated proteins in the GuHCl frac- tion and 87 in the NaCl fraction, with an Protein ID Fold change (log2) FDR Gene Protein name NaCl fraction overlap of 51 (Supplemental Table 2). S10A9_HUMAN 1.10 0.004 S100A9 Protein S100-A9 When comparing carotid plaques OSTP_HUMAN 1.38 0.005 SPP1 Osteopontin from symptomatic and asymptomatic S10A8_HUMAN 0.68 0.019 S100A8 Protein S100-A8
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