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UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity
Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an aut...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320807/ https://www.ncbi.nlm.nih.gov/pubmed/28225086 http://dx.doi.org/10.1038/srep43251 |
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author | An, Lin Hu, Xiao-wen Zhang, Shasha Hu, Xiaowen Song, Zongpei Naz, Amber Zi, Zhenguo Wu, Jian Li, Can Zou, Yunzeng He, Lin Zhu, Hongxin |
author_facet | An, Lin Hu, Xiao-wen Zhang, Shasha Hu, Xiaowen Song, Zongpei Naz, Amber Zi, Zhenguo Wu, Jian Li, Can Zou, Yunzeng He, Lin Zhu, Hongxin |
author_sort | An, Lin |
collection | PubMed |
description | Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. |
format | Online Article Text |
id | pubmed-5320807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53208072017-03-01 UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity An, Lin Hu, Xiao-wen Zhang, Shasha Hu, Xiaowen Song, Zongpei Naz, Amber Zi, Zhenguo Wu, Jian Li, Can Zou, Yunzeng He, Lin Zhu, Hongxin Sci Rep Article Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. Nature Publishing Group 2017-02-22 /pmc/articles/PMC5320807/ /pubmed/28225086 http://dx.doi.org/10.1038/srep43251 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article An, Lin Hu, Xiao-wen Zhang, Shasha Hu, Xiaowen Song, Zongpei Naz, Amber Zi, Zhenguo Wu, Jian Li, Can Zou, Yunzeng He, Lin Zhu, Hongxin UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title | UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title_full | UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title_fullStr | UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title_full_unstemmed | UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title_short | UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity |
title_sort | uvrag deficiency exacerbates doxorubicin-induced cardiotoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320807/ https://www.ncbi.nlm.nih.gov/pubmed/28225086 http://dx.doi.org/10.1038/srep43251 |
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