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De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

  • Author Footnotes
    1 These authors contributed equally to this work.
    Concetta Schiano
    Correspondence
    Corresponding author. University of Campania "Luigi Vanvitelli" Department of Advanced Medical and Surgical Sciences Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania L. Vanvitelli, Naples, Italy, Cellular and Molecular Cardiology lab Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland Piazza Miraglia 2, 80138, Naples, Italy.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, Naples, Italy

    Cellular and Molecular Cardiology lab Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland

    Laboratories for Translation Research, EOC, Bellinzona, Switzerland
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Carolina Balbi
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cellular and Molecular Cardiology lab Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland

    Laboratories for Translation Research, EOC, Bellinzona, Switzerland

    Center for Molecular Cardiology, Zurich, Switzerland
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  • Jacopo Burrello
    Affiliations
    Laboratories for Translation Research, EOC, Bellinzona, Switzerland

    Cardiovascular Theranostics, Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland
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  • Antonio Ruocco
    Affiliations
    Unit of Cardiovascular Diseases and Arrhythmias, Antonio Cardarelli Hospital, Naples, Italy
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  • Teresa Infante
    Affiliations
    Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, Naples, Italy
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  • Carmela Fiorito
    Affiliations
    Azienda Universitaria Policlinico (AOU), Naples, Italy
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  • Stefano Panella
    Affiliations
    Laboratories for Translation Research, EOC, Bellinzona, Switzerland

    Cardiovascular Theranostics, Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland
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  • Lucio Barile
    Affiliations
    Laboratories for Translation Research, EOC, Bellinzona, Switzerland

    Cardiovascular Theranostics, Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland
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  • Ciro Mauro
    Affiliations
    Unit of Cardiovascular Diseases and Arrhythmias, Antonio Cardarelli Hospital, Naples, Italy
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  • Author Footnotes
    2 These authors share the senior authorship.
    Giuseppe Vassalli
    Footnotes
    2 These authors share the senior authorship.
    Affiliations
    Cellular and Molecular Cardiology lab Istituto Cardiocentro Ticino-EOC, Lugano, Switzerland

    Laboratories for Translation Research, EOC, Bellinzona, Switzerland

    Center for Molecular Cardiology, Zurich, Switzerland
    Search for articles by this author
  • Author Footnotes
    2 These authors share the senior authorship.
    Claudio Napoli
    Footnotes
    2 These authors share the senior authorship.
    Affiliations
    Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, Naples, Italy

    Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Universitaria Policlinico (AOU), Naples, Italy
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 These authors share the senior authorship.

      Highlights

      • DNA methylation is associated with gene silencing, but its clinical role in cardiovascular diseases (CVDs) is not clear.
      • Extracellular vesicles are a potential non-invasive diagnostic liquid biopsy.
      • Extracellular vesicles can carry epigenetic modifications.
      • Acute coronary syndrome (ACS)-derived extracellular vesicles showed increased levels of DNA methyltransferases.
      • Extracellular vesicles modulate gene expression through de novo DNA methylation.

      Abstract

      Background and aims

      DNA methylation is associated with gene silencing, but its clinical role in cardiovascular diseases (CVDs) remains to be elucidated. We hypothesized that extracellular vesicles (EVs) may carry epigenetic changes, showing themselves as a potentially valuable non-invasive diagnostic liquid biopsy. We isolated and characterized circulating EVs of acute coronary syndrome (ACS) patients and assessed their role on DNA methylation in epigenetic modifications.

      Methods

      EVs were recovered from plasma of 19 ACS patients and 50 healthy subjects (HS). Flow cytometry, qRT-PCR, and Western blot (WB) were performed to evaluate both intra-vesicular and intra-cellular signals. ShinyGO, PANTHER, and STRING tools were used to perform GO and PPI network analyses.

      Results

      ACS-derived EVs showed increased levels of DNA methyltransferases (DNMTs) (p<0.001) and Ten-eleven translocation (TET) genes reduction. Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B, were significantly increased in plasma ACS-EVs. DNA methylation analysis on PBMCs from healthy donors treated with HS- and ACS-derived EVs showed an important role of DNMTs carried by EVs. PPI network analysis evidenced that ACS-EVs induced changes in PBMC methylome. In the most enriched subnetwork, the hub gene SRC was connected to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, BAIAP2 genes that were showed to have many molecular effects on various cell types into onset of several CVDs. Modulation in gene expression after ACS-EVs treatment was confirmed for SRC, NOTCH1, FOXO3, RXRA, DGKG and BAIAP2 (p<0.05).

      Conclusions

      Our data showed an important role for ACS-derived EVs in gene expression modulation through de novo DNA methylation signals, and modulating signalling pathways in target cells.

      Graphical abstract

      Keywords

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