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


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


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