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Multi-Omics’ Defines Unstable and Stable Atherosclerotic Plaque Signatures and Identifies Novel Targets for Plaque Stabilisation

ABSTRACT: The rupture of unstable atherosclerotic plaques, leading to debilitating or fatal thrombotic events, are a major health concern worldwide. Limited understanding as to the molecular drivers of plaque destabilisation and rupture hinders efforts in diagnosis and treatment prior to thrombotic events. Using an advanced pre-clinical model (tandem stenosis), we characterise the molecular signatures associated with plaque instability in atherosclerotic vessels.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: david greening

LAB HEAD: David Greening

PROVIDER: PXD018224 | Pride | 2023-07-24

REPOSITORIES: Pride

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			Action	DRS
	20150402VS03_21.raw	Raw
	20150402VS04_26.raw	Raw
	20150402VS05_31.raw	Raw
	20150402VS06_36.raw	Raw
	20150402VS07_1.raw	Raw

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Publications

Quantitative proteomic landscape of unstable atherosclerosis identifies molecular signatures and therapeutic targets for plaque stabilization.

Chen Yung-Chih YC Smith Meaghan M Ying Ya-Lan YL Makridakis Manousos M Noonan Jonathan J Kanellakis Peter P Rai Alin A Salim Agus A Murphy Andrew A Bobik Alex A Vlahou Antonia A Greening David W DW Peter Karlheinz K

Communications biology 20230313 1

Atherosclerotic plaque rupture leading to myocardial infarction is a major global health burden. Applying the tandem stenosis (TS) mouse model, which distinctively exhibits the characteristics of human plaque instability/rupture, we use quantitative proteomics to understand and directly compare unstable and stable atherosclerosis. Our data highlight the disparate natures and define unique protein signatures of unstable and stable atherosclerosis. Key proteins and pathway networks are identified ...[more]

PMID: 36914713

Similar Datasets

Unstable Atherosclerotic Plaque Proteome

Project description:The rupture of unstable atherosclerotic plaques, leading to debilitating or fatal thrombotic events, is a major health burden worldwide. Limited understanding as to the molecular drivers of plaque instability and rupture hinders efforts in diagnosis and treatment prior to thrombotic events. Utilising an advanced pre-clinical mouse model (Tandem stenosis (TS) model), which presents human-like unstable atherosclerotic disease, we apply high-end omic methods to characterize the molecular signatures associated with plaque instability in atherosclerotic arteries. Through quantitative proteomic profiling, we depict unique proteome signatures of unstable plaques compared to stable plaques and healthy arteries. Coupled with single-cell RNA-sequencing of leukocytes, we describe the heterodimer complex S100a8/S100a9 as unique to unstable plaque, with neutrophils implicated as the transcriptional drivers of S100a8/a9 expression. We confirm S100a9 expression in human carotid atherosclerotic plaques and we further utilise the TS pre-clinical model to pharmacologically inhibit S100a8/S100a9, resulting in plaque stabilisation. Thus, we establish the TS model as a sophisticated translational tool for the profiling of unstable atherosclerotic plaques and demonstrate that unstable and stable atherosclerosis are highly different disease entities.

2023-05-10 | PXD030857 | Pride

Multi-platform approach for plaque-derived biomarkers for the vulnerable plaque. Challenges and promises.

Project description:Plaque rupture and subsequent thrombus formation is responsible for the majority of clinical complications of atherosclerosis and nonetheless our understanding of what underlies plaque vulnerability and rupture is still sparse and mostly deductively based on animal models and in vitro studies. We adopted five different -omics platforms to compare ruptured atherosclerotic and advanced-stable tissue within the same carotid plaque specimen from 24 carotid endarterectomy patients. Segments designated as stable feature either a fibrous cap atheroma or pathological intimal thickening. Segments designated as ruptured include a thrombus and/or presented intraplaque hemorrhage. For the present study only those samples were selected for further analysis that were flanked by two segments of identical classification, be it stable (S) or ruptured (R); and were derived from CEA specimen that contained plaque segments of both classifications.

2014-05-17 | E-MTAB-2055 | biostudies-arrayexpress

Expression data from laser capture microdissected human atherosclerotic plaque, rich or void of plasmacytoid dendritic cells

Project description:Plasmacytoid dendritic cells (pDCs) are scarcely present in the inflamed human atherosclerotic plaque, where they are presumed to exert pro-inflammatory functions through release of type I interferons. However, the precise role of pDCs in human atherosclerosis yet remains to be established. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. We investigated the impact of human plaque pDCs on its local context, applying state of the art transcriptomics analysis on Laser Capture Microdissected fractions of human atherosclerotic plaques, distinctively enriched in pDCs, or pDCs-void.

2013-08-26 | E-GEOD-49670 | biostudies-arrayexpress

LncRNA expression in the formation of carotid plaque caused by atherosclerosis

Project description:Atherosclerotic plaques belong to the common vascular disease in the aged, which rupture will lead to acute thromboembolic diseases, the major reason for fatal cardiovascular events. Accumulating evidence indicates that lncRNAs exert critical functions in atherosclerosis. To identify novel astherosclerotic plaques-relevant lncRNAs, four specimens of carotid atherosclerotic plaque were collected, and endovascular tissue one centimeter far from the carotid atherosclerotic plaque was taken as a control group, we performed lncRNA microarray analysis using Affymetrix Human OElncRNA

2022-07-01 | GSE207252 | GEO

Destabilization of atherosclerotic plaque by bilirubin deficiency

Project description:The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease (CVD). Plasma concentrations of bilirubin, a by-product of heme catabolism, inversely associate with risk of CVD, although the link between bilirubin and atherosclerosis remains unclear.

2024-02-22 | PXD040314 | JPOST Repository

Genes in unstable plaques

Project description:Transcriptional profiling of stable and unstable atherosclerotic plaque segments from human carotid endatrerectomies Objective Comparison of gene expression in stable versus unstable atherosclerotic plaque may be confounded by interpatient variability. The aim of this study was to identify differences in gene expression between stable and unstable segments of plaque obtained from the same patient. Human carotid endarterectomy specimens were segmented and macroscopically classified using a morphological classification system. Two analytical methods, an intraplaque and an interplaque analysis, revealed 170 and 1916 differentially expressed genes, respectively using Affymetrix gene chip analysis. A total of 115 genes were identified from both analyses. The differential expression of 27 genes was also confirmed using quantitative-polymerase chain reaction on a larger panel of samples. Eighteen of these genes have not been associated previously with plaque instability, including the metalloproteinase, ADAMDEC1 (37-fold), retinoic acid receptor responder-1 (5-fold), and cysteine protease legumain (3-fold). Matrix metalloproteinase-9 (MMP-9), cathepsin B, and a novel gene, legumain, a potential activator of MMPs and cathepsins, were also confirmed at the protein level. The differential expression of 18 genes not previously associated with plaque rupture has been confirmed in stable and unstable regions of the same atherosclerotic plaque. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability. Differential gene expression in stable and unstable plaque was assessed by whole transcriptome analysis. Intraplaque analysis by QT-PCR confirmed the differential expression of 18 genes not associated previously with plaque rupture. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability

2006-01-30 | E-TABM-190 | biostudies-arrayexpress

Gene expression profiling of human atherosclerotic plaque

Project description:This SuperSeries is composed of the following subset Series: GSE23303: Gene expression profiling of human atherosclerotic plaque: Laser capture microscopy of smooth muscle cells and macrophages GSE23304: Gene expression profiling of human atherosclerotic plaque: 101 peripheral plaques GSE24495: Gene expression profiling of human atherosclerotic plaque: Carotid plaque GSE24702: Gene expression profiling of human atherosclerotic plaque: 290 peripheral plaques Refer to individual Series

2011-09-30 | E-GEOD-23314 | biostudies-arrayexpress

Proteomic analysis of human atherosclerotic plaque supernatants in response to treatment with monocyte extracellular vesicles

Project description:Extracellular vesicles (EV) convey biological messages through their cargoes. Herein we focus on monocyte/platelet aggregates characteristic of several cardiovascular diseases with an analysis of monocyte-derived EV (mEVs) effects on the atherosclerotic plaque. Monocyte preparations were stimulated with TNF-α in presence or absence of prostacyclin and EVs isolated via centrifugation. EV physical characteristics were determined by Nanoparticle Tracking analysis while surface profile was analysed using imaging flow cytometry. Atherosclerotic plaques from 5 patients undergoing endarterectomy were cultured with or without mEVs. Cytokines and proteins released in the culture media were measured by multiplex ELISA and mass spectrometry. Proteomic of mEVs prepared in different incubation settings was also conducted. Monocyte isolation yielded ~80% platelet-monocyte aggregates. TNF-α stimulation produced CD14+ EVs as well as a subset bearing the CD41 marker for platelets (CD14+/CD41+). Prostacyclin addition did not modulate monocyte/platelet aggregates, but impacted on mEV numbers. Addition of TNF-α mEVs on atherosclerotic plaque fragments impacted on general protein release (19 upregulated and 7 downregulated) and elevated cytokine release. mEVs generated by TNF-α and prostacyclin produced minimal changes on plaque reactivity. Proteomic analysis of mEVs revealed a distinctive composition when the cell preparation was activated with TNF-α alone or with prostacyclin. In conclusion, mEVs activate the atherosclerotic plaque. Attenuating platelet activation has an effect on EV composition with downstream modulation of their pro-inflammatory actions. EV heterogeneity reflects the mode of activation of the cell of origin and may differently contribute to the development and progression of atherosclerosis.

2021-09-08 | PXD014324 | Pride

Microarray of ApoE deficient mice atherosclerotic plaque macrophages from Streptococcus pneumoniae infected mice compared to mock infected controls

Project description:Transcriptional profiling of aortic sinus atherosclerotic plaque macrophages obtained by laser capture microdissection from male ApoE deficient mice infected with 5x10(5) cfu serotype 4 Streptococcus pneumoniae via intranasal instillation (n=9) as compared with mice mock infected with PBS (n=11). Mice were culled 2 weeks post infection/mock infection.

2022-02-15 | E-MTAB-11462 | biostudies-arrayexpress

Gene expression profiling of human atherosclerotic plaque: Carotid plaque

Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies. 6 human carotid plaques were sectioned in 1 mm thick slices. Alternative slices were used for gene expression profiling in Affymetrix/Merck custom 1.0 arrays (GPL10687), or for immunohistochemistry studies (CD68, Actin)

2011-09-30 | E-GEOD-24495 | biostudies-arrayexpress

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