Dataset Information

Quantitative proteomic analysis of the human extracellular vesicle proteome reveals a novel mechanism for tissue cross-talk during exercise

ABSTRACT: Exercise stimulates the release of a plethora of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognising that many circulating proteins might be packaged in extracellular vesicles (EV), we employed quantitative proteomic techniques to characterise the exercise-induced secretion of EV contained proteins. We observed an increase in circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles, in human arterial blood samples. Pathway analyses revealed significant enrichments in a multitude of biological processes and signalling pathways. Pulse chase and intravital imaging experiments suggest EV-mediated muscle-liver cross talk during exercise. Moreover, by employing arterio-venous balance studies across the contracting human limb, we identified several novel candidate myokines. These data offer a new paradigm by which tissue cross-talk during exercise can exert systemic biological effects

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Blood Plasma, Cell Culture

SUBMITTER: Martin Whitham

LAB HEAD: Martin Whitham

PROVIDER: PXD006501 | Pride | 2018-01-10

REPOSITORIES: Pride

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Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise.

Whitham Martin M Parker Benjamin L BL Friedrichsen Martin M Hingst Janne R JR Hjorth Marit M Hughes William E WE Egan Casey L CL Cron Lena L Watt Kevin I KI Kuchel Rhiannon P RP Jayasooriah Navind N Estevez Emma E Petzold Tim T Suter Catherine M CM Gregorevic Paul P Kiens Bente B Richter Erik A EA James David E DE Wojtaszewski Jørgen F P JFP Febbraio Mark A MA

Cell metabolism 20180101 1

Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 3 ...[more]

PMID: 29320704

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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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