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Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity.

Authors
  • Milano, Giuseppina1, 2
  • Biemmi, Vanessa1, 3
  • Lazzarini, Edoardo1, 4, 5
  • Balbi, Carolina1
  • Ciullo, Alessandra1
  • Bolis, Sara1
  • Ameri, Pietro4, 5
  • Di Silvestre, Dario6
  • Mauri, Pierluigi6
  • Barile, Lucio1, 3
  • Vassalli, Giuseppe1, 3, 7
  • 1 Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, 6900 Lugano, Switzerland. , (Switzerland)
  • 2 Department of Cœur-Vaisseaux, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. , (Switzerland)
  • 3 Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. , (Switzerland)
  • 4 Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy. , (Italy)
  • 5 Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy. , (Italy)
  • 6 Proteomics and Metabolomic Lab, ITB-CNR, Departent of Biomedicine, 20090 Segrate, Italy. , (Italy)
  • 7 Center for Molecular Cardiology, University Hospital, Zürich, Switzerland. , (Switzerland)
Type
Published Article
Journal
Cardiovascular Research
Publisher
Oxford University Press
Publication Date
Feb 01, 2020
Volume
116
Issue
2
Pages
383–392
Identifiers
DOI: 10.1093/cvr/cvz108
PMID: 31098627
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Combined administration of anthracyclines (e.g. doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2), is an effective treatment for HER2-positive breast cancer. However, both agents are associated with cardiac toxicity. Human cardiac-resident mesenchymal progenitor cells (CPCs) secrete extracellular vesicles including nanosized exosomes which protect against myocardial ischaemia. Here, we investigated the effects of these exosomes using a novel model of Dox/Trz-mediated cardiotoxicity. CPCs were derived from cardiac atrial appendage specimens from patients who underwent heart surgery for heart valve disease and/or ischaemic heart disease, and exosomes were purified from CPC conditioned media. Proteomics analyses revealed that CPC exosomes contained multiple proteins involved in redox processes. Dox/Trz induced a significant increase in reactive oxygen species (ROS) in rat cardiomyocytes, which was prevented by CPC exosomes. In vivo, rats received six doses of Dox (Days 1-11), followed by six doses of Trz (Days 19-28). Three doses of either exosomes or exosome suspension vehicle were injected intravenously on Days 5, 11, and 19 in the treatment and control groups, respectively. Dox/Trz induced myocardial fibrosis, CD68+ inflammatory cell infiltrates, inducible nitric oxide synthase expression, and left ventricular dysfunction. CPC exosomes prevented these effects. These vesicles were highly enriched in miR-146a-5p compared with human dermal fibroblast exosomes. Dox upregulated Traf6 and Mpo, two known miR-146a-5p target genes (which encode signalling mediators of inflammatory and cell death axes) in myocytes. CPC exosomes suppressed miR-146a-5p target genes Traf6, Smad4, Irak1, Nox4, and Mpo in Dox-treated cells. Specific silencing of miR-146a-5p abrogated exosome-mediated suppression of those genes leading to an increase in Dox-induced cell death. Human CPC exosomes attenuate Dox-/Trz-induced oxidative stress in cardiomyocytes. Systemic administration of these vesicles prevents Dox/Trz cardiotoxicity in vivo. miR-146a-5p mediates some of the benefits of exosomes in this setting. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

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