Header

UZH-Logo

Maintenance Infos

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


Milano, Giuseppina; Biemmi, Vanessa; Lazzarini, Edoardo; Balbi, Carolina; Ciullo, Alessandra; Bolis, Sara; Ameri, Pietro; Di Silvestre, Dario; Mauri, Pierluigi; Barile, Lucio; Vassalli, Giuseppe (2020). Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity. Cardiovascular Research, 116(2):383-392.

Abstract

BACKGROUND
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 ischemia. 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 ischemic 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 6 doses of Dox (days 1-11), followed by 6 doses of Trz (days 19-28). Three doses of either exosomes or exosome suspension vehicle were injected intravenously on days 5, 11 and 19. Dox/Trz induced myocardial fibrosis, CD68+ inflammatory cell infiltrates, inducible nitric oxide synthase (iNOS) expression, and left ventricular (LV) dysfunction. CPC exosomes prevented these effects. These vesicles were highly enriched in miR-146a-5p compared with human dermal fibroblast exosomes. Dox upregulatedTraf6 and Mpo, two known miR-146a-5p target genes (which encode signaling mediators of inflammatory and cell death axes) in myocytes. CPC exosomes suppressed miR-146a-5p target genesTraf6, 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.

Abstract

BACKGROUND
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 ischemia. 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 ischemic 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 6 doses of Dox (days 1-11), followed by 6 doses of Trz (days 19-28). Three doses of either exosomes or exosome suspension vehicle were injected intravenously on days 5, 11 and 19. Dox/Trz induced myocardial fibrosis, CD68+ inflammatory cell infiltrates, inducible nitric oxide synthase (iNOS) expression, and left ventricular (LV) dysfunction. CPC exosomes prevented these effects. These vesicles were highly enriched in miR-146a-5p compared with human dermal fibroblast exosomes. Dox upregulatedTraf6 and Mpo, two known miR-146a-5p target genes (which encode signaling mediators of inflammatory and cell death axes) in myocytes. CPC exosomes suppressed miR-146a-5p target genesTraf6, 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.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Cardiocentro Ticino
04 Faculty of Medicine > Center for Molecular Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 February 2020
Deposited On:17 Jan 2020 09:33
Last Modified:28 Jan 2020 02:06
Publisher:Oxford University Press
ISSN:0008-6363
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvz108
PubMed ID:31098627

Download

Full text not available from this repository.
View at publisher

Get full-text in a library