Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways

English version

Autoři: Masatoshi Narikawa ^aff001; Masanari Umemura ^aff001; Ryo Tanaka ^aff001; Mayu Hikichi ^aff001; Akane Nagasako ^aff001; Takayuki Fujita ^aff001; Utako Yokoyama ^aff001; Tomoaki Ishigami ^aff002; Kazuo Kimura ^aff002; Kouichi Tamura ^aff002; Yoshihiro Ishikawa ^aff001
Působiště autorů: Cardiovascular Research Institute, Yokohama City University School of Medicine, Yokohama, Japan ^aff001; Medical Science and Cardiorenal Medicine, Yokohama City University School of Medicine, Yokohama, Japan ^aff002; Department of Physiology, Tokyo Medical University Graduate School of Medicine, Tokyo, Japan ^aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0221940

Souhrn

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.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Connective tissue cells – Fibroblasts – Signal transduction – Cell signaling – Signaling cascades – TGF-beta signaling cascade – Anatomy – Biological tissue – Connective tissue – Molecular biology – Molecular biology techniques – Molecular biology assays and analysis techniques – Gene expression and vector techniques – Protein expression – Physiology – Developmental biology – Molecular development – Biochemistry – Proteins – Collagens – Medicine and health sciences – Immune physiology – Immunology – Immune system – Innate immune system – Cytokines – Cardiology – Heart failure – Research and analysis methods – Bioassays and physiological analysis – Microarrays

Zdroje

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Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways

Souhrn

Klíčová slova:

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