Doxorubicin upregulates CXCR4 via miR-200c/ZEB1-dependent mechanism in human cardiac mesenchymal progenitor cells.

Details

Serval ID
serval:BIB_38337628DC5D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Doxorubicin upregulates CXCR4 via miR-200c/ZEB1-dependent mechanism in human cardiac mesenchymal progenitor cells.
Journal
Cell death & disease
Author(s)
Beji S., Milano G., Scopece A., Cicchillitti L., Cencioni C., Picozza M., D'Alessandra Y., Pizzolato S., Bertolotti M., Spaltro G., Raucci A., Piaggio G., Pompilio G., Capogrossi M.C., Avitabile D., Magenta A., Gambini E.
ISSN
2041-4889 (Electronic)
Publication state
Published
Issued date
24/08/2017
Peer-reviewed
Oui
Volume
8
Number
8
Pages
e3020
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor-cell depletion. Although the cardioprotective role of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF1/CXCR4) axis is well established, its involvement during DOXO-induced cardiotoxicity has never been investigated. We showed that in a mouse model of DOXO-induced cardiomyopathy, CXCR4 <sup>+</sup> cells were increased in response to DOXO, mainly in human cardiac mesenchymal progenitor cells (CmPC), a subpopulation with regenerative potential. Our in vitro results showed a CXCR4 induction after 24 h of DOXO exposure in CmPC. SDF1 administration protected from DOXO-induced cell death and promoted CmPC migration. CXCR4 promoter analysis revealed zinc finger E-box binding homeobox 1 (ZEB1) binding sites. Upon DOXO treatment, ZEB1 binding decreased and RNA-polymerase-II increased, suggesting a DOXO-mediated transcriptional increase in CXCR4. Indeed, DOXO induced the upregulation of miR-200c, that directly targets ZEB1. SDF1 administration in DOXO-treated mice partially reverted the adverse remodeling, decreasing left ventricular (LV) end diastolic volume, LV ejection fraction and LV anterior wall thickness in diastole, recovering LV end systolic pressure and reducing±dP/dt. Moreover, in vivo administration of SDF1 partially reverted DOXO-induced miR-200c and p53 protein upregulation in mouse hearts. In addition, downmodulation of ZEB1 mRNA and protein by DOXO was significantly increased by SDF1. In keeping, p21 mRNA, that is induced by p53 and inhibited by ZEB1, is induced by DOXO treatment and is decreased by SDF1 administration. This study showed new players of the DOXO-induced cardiotoxicity, that can be exploited to ameliorate DOXO-associated cardiomyopathy.
Keywords
Animals, Doxorubicin/pharmacology, Female, Humans, Mesenchymal Stromal Cells/drug effects, Mesenchymal Stromal Cells/metabolism, Mice, Mice, Inbred C57BL, MicroRNAs/genetics, MicroRNAs/metabolism, Receptors, CXCR4/genetics, Receptors, CXCR4/metabolism, Signal Transduction, Up-Regulation/drug effects, Zinc Finger E-box-Binding Homeobox 1/genetics, Zinc Finger E-box-Binding Homeobox 1/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
29/09/2017 11:15
Last modification date
20/08/2019 14:26
Usage data