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LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells an...

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Autores principales: Miyoshi, Toru, Nakamura, Kazufumi, Amioka, Naofumi, Hatipoglu, Omer F., Yonezawa, Tomoko, Saito, Yukihiro, Yoshida, Masashi, Akagi, Satoshi, Ito, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943022/
https://www.ncbi.nlm.nih.gov/pubmed/35322164
http://dx.doi.org/10.1038/s41598-022-09094-z
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author Miyoshi, Toru
Nakamura, Kazufumi
Amioka, Naofumi
Hatipoglu, Omer F.
Yonezawa, Tomoko
Saito, Yukihiro
Yoshida, Masashi
Akagi, Satoshi
Ito, Hiroshi
author_facet Miyoshi, Toru
Nakamura, Kazufumi
Amioka, Naofumi
Hatipoglu, Omer F.
Yonezawa, Tomoko
Saito, Yukihiro
Yoshida, Masashi
Akagi, Satoshi
Ito, Hiroshi
author_sort Miyoshi, Toru
collection PubMed
description Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague–Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.
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spelling pubmed-89430222022-03-28 LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats Miyoshi, Toru Nakamura, Kazufumi Amioka, Naofumi Hatipoglu, Omer F. Yonezawa, Tomoko Saito, Yukihiro Yoshida, Masashi Akagi, Satoshi Ito, Hiroshi Sci Rep Article Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague–Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress. Nature Publishing Group UK 2022-03-23 /pmc/articles/PMC8943022/ /pubmed/35322164 http://dx.doi.org/10.1038/s41598-022-09094-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Miyoshi, Toru
Nakamura, Kazufumi
Amioka, Naofumi
Hatipoglu, Omer F.
Yonezawa, Tomoko
Saito, Yukihiro
Yoshida, Masashi
Akagi, Satoshi
Ito, Hiroshi
LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title_full LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title_fullStr LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title_full_unstemmed LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title_short LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
title_sort lcz696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943022/
https://www.ncbi.nlm.nih.gov/pubmed/35322164
http://dx.doi.org/10.1038/s41598-022-09094-z
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