Dataset Information

A combination of proteomic approaches identifies a panel of circulating extracellular vesicle proteins related to the risk of suffering cardiovascular disease in obese patients

ABSTRACT: Plasma-derived extracellular vesicles (EVs) have been extensively described as putative biomarkers in different diseases. More precisely, increased levels of EVs subpopulations are well-known to associate with obesity. The goal of this study was to identify EVs-derived biomarkers in plasma from obese patients in order to predict the development of pathological events associated with obesity. The study was performed combining two different proteomic approaches (2D-DIGE and label-free LC-MS/MS). Samples were obtained from 22 obese patients, with no associated comorbidities, and their lean-matched controls. EVs were isolated following a serial ultracentrifugation protocol. We detected 22 and 23 different regulated protein features from 2D-DIGE and label free LC-MS/MS respectively. Most of the differentially regulated proteins identified were involved in the coagulation and complement cascade. Interestingly, there was a clear up-regulation of complement C3, complement C4 and fibrinogen in obese patients following both approaches, which correlates with a pro-inflammatory and prothrombotic state of those individuals. On the other hand, we showed a down-regulation of adiponectin leading to an increased risk of suffering cardiovascular diseases. Our results suggest the relevance of considering plasma-derived-EVs proteins as a source of potential biomarkers for the development of atherothrombotic events in obesity.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Obesity

SUBMITTER: María Núñez

LAB HEAD: Maria N. Barrachina

PROVIDER: PXD010404 | Pride | 2018-12-17

REPOSITORIES: Pride

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A Combination of Proteomic Approaches Identifies A Panel of Circulating Extracellular Vesicle Proteins Related to the Risk of Suffering Cardiovascular Disease in Obese Patients.

Barrachina María N MN Sueiro Aurelio M AM Casas Vanessa V Izquierdo Irene I Hermida-Nogueira Lidia L Guitián Esteban E Casanueva Felipe F FF Abián Joaquín J Carrascal Montserrat M Pardo María M García Ángel Á

Proteomics 20181227 1-2

Plasma-derived extracellular vesicles (EVs) have been extensively described as putative biomarkers in different diseases. Interestingly, increased levels of EVs subpopulations are well known to associate with obesity. The goal of this study is to identify EVs-derived biomarkers in plasma from obese patients in order to predict the development of pathological events associated with obesity. Samples are obtained from 22 obese patients and their lean-matched controls are divided into two cohorts: o ...[more]

PMID: 30536591

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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