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The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes

Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we ass...

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Autores principales: Liu, Shu-Ting, Huang, Shih-Ming, Ho, Ching-Liang, Yen, Li-Chen, Huang, Chi-Jung, Lin, Wei-Shiang, Chan, James Yi-Hsin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741940/
https://www.ncbi.nlm.nih.gov/pubmed/26452256
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author Liu, Shu-Ting
Huang, Shih-Ming
Ho, Ching-Liang
Yen, Li-Chen
Huang, Chi-Jung
Lin, Wei-Shiang
Chan, James Yi-Hsin
author_facet Liu, Shu-Ting
Huang, Shih-Ming
Ho, Ching-Liang
Yen, Li-Chen
Huang, Chi-Jung
Lin, Wei-Shiang
Chan, James Yi-Hsin
author_sort Liu, Shu-Ting
collection PubMed
description Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression.
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spelling pubmed-47419402016-03-17 The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes Liu, Shu-Ting Huang, Shih-Ming Ho, Ching-Liang Yen, Li-Chen Huang, Chi-Jung Lin, Wei-Shiang Chan, James Yi-Hsin Oncotarget Research Paper Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression. Impact Journals LLC 2015-10-07 /pmc/articles/PMC4741940/ /pubmed/26452256 Text en Copyright: © 2015 Liu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Liu, Shu-Ting
Huang, Shih-Ming
Ho, Ching-Liang
Yen, Li-Chen
Huang, Chi-Jung
Lin, Wei-Shiang
Chan, James Yi-Hsin
The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title_full The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title_fullStr The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title_full_unstemmed The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title_short The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
title_sort regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741940/
https://www.ncbi.nlm.nih.gov/pubmed/26452256
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