PXD031052

PXD031052 is an original dataset announced via ProteomeXchange.

Title	A Proteomic Atlas of Atherosclerosis: Regional Proteomic Signatures for Plaque Inflammation and Calcification
Description	Background: Using proteomics, we strove to reveal novel molecular subtypes of human atherosclerotic lesions, study their associations with histology and imaging and relate them to long-term cardiovascular outcomes. Methods: 219 samples were obtained from 120 patients undergoing carotid endarterectomy. Sequential protein extraction was combined with multiplexed, discovery proteomics. Parallel reaction monitoring for 135 proteins was deployed for targeted validation. A combination of statistical, bioinformatics and machine learning methods was used to perform differential expression, network, pathway enrichment analysis and train and evaluate prognostic models. Results: Our extensive proteomics analysis from the core and periphery of plaques doubled the coverage of the plaque proteome compared to the largest proteomics study on atherosclerosis thus far. Plaque inflammation and calcification signatures were inversely correlated and validated with targeted proteomics. The inflammation signature was enriched with neutrophil-derived proteins, including calprotectin (S100A8/9) and myeloperoxidase. The calcification signature contained fetuin-A, osteopontin, and gamma-carboxylated proteins. Sex differences in the proteome of atherosclerosis were explained by a higher proportion of calcified plaques in women. Single-cell RNA sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages and the calcification signature to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in the plaque, i.e., fetuin-A. Echogenic lesions reflect the collagen content and calcification of plaque but carotid Duplex ultrasound fails to capture the extent of inflammatory protein changes in symptomatic plaques. Applying dimensionality reduction and machine learning on the proteomics data defined 4 distinct plaque phenotypes and revealed key protein signatures linked to smooth muscle cell content, plaque calcification and structural extracellular matrix, which improved the 9-year prognostic AUC by 25% compared to ultrasound and histology. A biosignature of four proteins (CNN1, PROC, SERPH, and CSPG2) independently predicted the progression of atherosclerosis and cardiovascular mortality with an AUC of 75% Conclusion: We combined discovery and targeted proteomics with network reconstruction and clustering techniques to provide molecular insights into protein changes in atherosclerotic plaques. The application of proteomics and machine learning techniques revealed distinct clusters of plaques that inform on disease progression and future adverse cardiovascular events.
HostingRepository	PRIDE
AnnounceDate	2023-11-15
AnnouncementXML	Submission_2023-11-15_04:01:35.854.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoke Yin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-18 02:23:36	ID requested
⏵ 1	2023-11-15 04:01:36	announced

Theofilatos K, Stojkovic S, Hasman M, van der Laan SW, Baig F, Barallobre-Barreiro J, Schmidt LE, Yin S, Yin X, Burnap S, Singh B, Popham J, Harkot O, Kampf S, Nackenhorst MC, Strassl A, Loewe C, Demyanets S, Neumayer C, Bilban M, Hengstenberg C, Huber K, Pasterkamp G, Wojta J, Mayr M, Proteomic Atlas of Atherosclerosis: The Contribution of Proteoglycans to Sex Differences, Plaque Phenotypes, and Outcomes. Circ Res, 133(7):542-558(2023) [pubmed]

submitter keyword: Calcification, TMT-labelling, Plaque, Cardiovascular Outcome Prognosis,Atherosclerosis, Inflammation, Carotid Endarterectomy

Manuel Mayr
contact affiliation	King's BHF Centre, King's College London, London, UK
contact email	manuel.mayr@kcl.ac.uk
lab head
Xiaoke Yin
contact affiliation	Cardiovascular Division, King's College London
contact email	xiaoke.yin@kcl.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/11/PXD031052

PRIDE project URI

• PRIDE
  1. PXD031052
     1. Label: PRIDE project
     2. Name: A Proteomic Atlas of Atherosclerosis: Regional Proteomic Signatures for Plaque Inflammation and Calcification