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Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway
BACKGROUND: Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erbα is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erbα in doxorubicin-induced cardiotoxi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977526/ https://www.ncbi.nlm.nih.gov/pubmed/36874248 http://dx.doi.org/10.1155/2023/2108584 |
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author | Zou, Runmei Wang, Shuo Cai, Hong Wang, Yuwen Wang, Cheng |
author_facet | Zou, Runmei Wang, Shuo Cai, Hong Wang, Yuwen Wang, Cheng |
author_sort | Zou, Runmei |
collection | PubMed |
description | BACKGROUND: Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erbα is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erbα in doxorubicin-induced cardiotoxicity. METHODS: H9c2 cells were treated with 1.5 μM doxorubicin, and C57BL/6 mice were treated with a 20 mg/kg cumulative dose of doxorubicin to construct doxorubicin-induced cardiotoxicity models in vitro and in vivo. Agonist SR9009 was used to activate Rev-erbα. PGC-1α expression level was downregulated by specific siRNA in H9c2 cells. Cell apoptosis, cardiomyocyte morphology, mitochondrial function, oxidative stress, and signaling pathways were measured. RESULTS: SR9009 alleviated doxorubicin-induced cell apoptosis, morphological disorder, mitochondrial dysfunction, and oxidative stress in H9c2 cells and C57BL/6 mice. Meanwhile, PGC-1α and downstream signaling NRF1, TAFM, and UCP2 expression levels were preserved by SR9009 in doxorubicin-treated cardiomyocytes in vitro and in vivo. When downregulating PGC-1α expression level by specific siRNA, the protective role of SR9009 in doxorubicin-treated cardiomyocytes was attenuated with increased cell apoptosis, mitochondrial dysfunction, and oxidative stress. CONCLUSION: Pharmacological activation of Rev-erbα by SR9009 could attenuate doxorubicin-induced cardiotoxicity through preservation of mitochondrial function and alleviation of apoptosis and oxidative stress. The mechanism is associated with the activation of PGC-1α signaling pathways, suggesting that PGC-1α signaling is a mechanism for the protective effect of Rev-erbα against doxorubicin-induced cardiotoxicity. |
format | Online Article Text |
id | pubmed-9977526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-99775262023-03-02 Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway Zou, Runmei Wang, Shuo Cai, Hong Wang, Yuwen Wang, Cheng Cardiovasc Ther Research Article BACKGROUND: Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erbα is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erbα in doxorubicin-induced cardiotoxicity. METHODS: H9c2 cells were treated with 1.5 μM doxorubicin, and C57BL/6 mice were treated with a 20 mg/kg cumulative dose of doxorubicin to construct doxorubicin-induced cardiotoxicity models in vitro and in vivo. Agonist SR9009 was used to activate Rev-erbα. PGC-1α expression level was downregulated by specific siRNA in H9c2 cells. Cell apoptosis, cardiomyocyte morphology, mitochondrial function, oxidative stress, and signaling pathways were measured. RESULTS: SR9009 alleviated doxorubicin-induced cell apoptosis, morphological disorder, mitochondrial dysfunction, and oxidative stress in H9c2 cells and C57BL/6 mice. Meanwhile, PGC-1α and downstream signaling NRF1, TAFM, and UCP2 expression levels were preserved by SR9009 in doxorubicin-treated cardiomyocytes in vitro and in vivo. When downregulating PGC-1α expression level by specific siRNA, the protective role of SR9009 in doxorubicin-treated cardiomyocytes was attenuated with increased cell apoptosis, mitochondrial dysfunction, and oxidative stress. CONCLUSION: Pharmacological activation of Rev-erbα by SR9009 could attenuate doxorubicin-induced cardiotoxicity through preservation of mitochondrial function and alleviation of apoptosis and oxidative stress. The mechanism is associated with the activation of PGC-1α signaling pathways, suggesting that PGC-1α signaling is a mechanism for the protective effect of Rev-erbα against doxorubicin-induced cardiotoxicity. Hindawi 2023-02-22 /pmc/articles/PMC9977526/ /pubmed/36874248 http://dx.doi.org/10.1155/2023/2108584 Text en Copyright © 2023 Runmei Zou et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Zou, Runmei Wang, Shuo Cai, Hong Wang, Yuwen Wang, Cheng Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title | Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title_full | Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title_fullStr | Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title_full_unstemmed | Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title_short | Pharmacological Activation of Rev-erbα Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1α Signaling Pathway |
title_sort | pharmacological activation of rev-erbα attenuates doxorubicin-induced cardiotoxicity by pgc-1α signaling pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977526/ https://www.ncbi.nlm.nih.gov/pubmed/36874248 http://dx.doi.org/10.1155/2023/2108584 |
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