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

Giuseppina Milano, Vanessa Biemmi, Edoardo Lazzarini, Carolina Balbi, Alessandra Ciullo, Sara Bolis, Pietro Ameri, Dario Di Silvestre, Pierluigi Mauri, Lucio Barile, Giuseppe Vassalli

Research output: Contribution to journalArticle

Abstract

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalCardiovascular Research
Volume116
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

Keywords

  • Anthracyclines
  • Cardiotoxicity
  • Doxorubicin
  • Exosomes
  • Trastuzumab

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Milano, G., Biemmi, V., Lazzarini, E., Balbi, C., Ciullo, A., Bolis, S., Ameri, P., Di Silvestre, D., Mauri, P., Barile, L., & Vassalli, G. (2020). Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity. Cardiovascular Research, 116(2), 383-392. https://doi.org/10.1093/cvr/cvz108