Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways.
Actins
/ metabolism
Animals
Cell Survival
/ drug effects
Cell Transdifferentiation
/ drug effects
Cells, Cultured
Collagen
/ metabolism
Doxorubicin
/ pharmacology
Fibroblasts
/ cytology
Gene Expression Profiling
Gene Expression Regulation
/ drug effects
Humans
Interleukin-6
/ metabolism
Matrix Metalloproteinase 1
/ genetics
Matrix Metalloproteinase 13
/ genetics
Mice
Myocytes, Cardiac
/ cytology
Organ Specificity
Signal Transduction
/ drug effects
Species Specificity
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
18
02
2019
accepted:
19
08
2019
entrez:
13
9
2019
pubmed:
13
9
2019
medline:
17
3
2020
Statut:
epublish
Résumé
Although doxorubicin (DOX)-induced cardiomyopathy causes lethal heart failure (HF), no early detection or effective treatment methods are available. The principal mechanisms of cardiotoxicity are considered to involve oxidative stress and apoptosis of cardiomyocytes. However, the effect of DOX on cardiac fibroblasts at non-lethal concentrations remains unknown. The aim of this study was to investigate the direct effect of doxorubicin on the activation of cardiac fibroblasts independent of cell death pathways. We first found that DOX induced α-SMA expression (marker of trans-differentiation) at a low concentration range, which did not inhibit cell viability. DOX also increased MMP1, IL-6, TGF-β and collagen expression in human cardiac fibroblasts (HCFs). In addition, DOX promoted Akt and Smad phosphorylation. A Smad inhibitor prevented DOX-induced α-SMA and IL-6 protein expression. An PI3K inhibitor also prevented MMP1 mRNA expression in HCFs. These findings suggest that DOX directly induces fibrotic changes in HCFs via cell death-independent pathways. Furthermore, we confirmed that these responses are organ- and species-specific for HCFs based on experiments using different types of human and murine fibroblast cell lines. These results suggest potentially new mechanisms of DOX-induced cardiotoxicity from the viewpoint of fibrotic changes in cardiac fibroblasts.
Identifiants
pubmed: 31513610
doi: 10.1371/journal.pone.0221940
pii: PONE-D-19-04752
pmc: PMC6742217
doi:
Substances chimiques
Actins
0
Interleukin-6
0
Doxorubicin
80168379AG
Collagen
9007-34-5
Matrix Metalloproteinase 13
EC 3.4.24.-
Mmp13 protein, mouse
EC 3.4.24.-
MMP1 protein, human
EC 3.4.24.7
Matrix Metalloproteinase 1
EC 3.4.24.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0221940Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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