Titre
Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Milano, G.
Auteure/Auteur
Biemmi, V.
Auteure/Auteur
Lazzarini, E.
Auteure/Auteur
Balbi, C.
Auteure/Auteur
Ciullo, A.
Auteure/Auteur
Bolis, S.
Auteure/Auteur
Ameri, P.
Auteure/Auteur
Di Silvestre, D.
Auteure/Auteur
Mauri, P.
Auteure/Auteur
Barile, L.
Auteure/Auteur
Vassalli, G.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1755-3245
Statut éditorial
Publié
Date de publication
2020-02-01
Volume
116
Numéro
2
Première page
383
Dernière page/numéro d’article
392
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
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.
PID Serval
serval:BIB_060A07C7529F
PMID
Date de création
2019-05-25T11:43:54.087Z
Date de création dans IRIS
2025-05-20T20:24:14Z
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Nom
cvz108.pdf
Version du manuscrit
preprint
Taille
1.2 MB
Format
Adobe PDF
PID Serval
serval:BIB_060A07C7529F.P001
Somme de contrôle
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