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All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity

The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesize...

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Autores principales: Hasbullah, Jafar S., Scott, Erika N., Bhavsar, Amit P., Gunaretnam, Erandika P., Miao, Fudan, Soliman, Hesham, Carleton, Bruce C., Ross, Colin J. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635745/
https://www.ncbi.nlm.nih.gov/pubmed/36331922
http://dx.doi.org/10.1371/journal.pone.0276541
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author Hasbullah, Jafar S.
Scott, Erika N.
Bhavsar, Amit P.
Gunaretnam, Erandika P.
Miao, Fudan
Soliman, Hesham
Carleton, Bruce C.
Ross, Colin J. D.
author_facet Hasbullah, Jafar S.
Scott, Erika N.
Bhavsar, Amit P.
Gunaretnam, Erandika P.
Miao, Fudan
Soliman, Hesham
Carleton, Bruce C.
Ross, Colin J. D.
author_sort Hasbullah, Jafar S.
collection PubMed
description The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway’s role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT.
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spelling pubmed-96357452022-11-05 All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity Hasbullah, Jafar S. Scott, Erika N. Bhavsar, Amit P. Gunaretnam, Erandika P. Miao, Fudan Soliman, Hesham Carleton, Bruce C. Ross, Colin J. D. PLoS One Research Article The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway’s role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT. Public Library of Science 2022-11-04 /pmc/articles/PMC9635745/ /pubmed/36331922 http://dx.doi.org/10.1371/journal.pone.0276541 Text en © 2022 Hasbullah et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hasbullah, Jafar S.
Scott, Erika N.
Bhavsar, Amit P.
Gunaretnam, Erandika P.
Miao, Fudan
Soliman, Hesham
Carleton, Bruce C.
Ross, Colin J. D.
All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title_full All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title_fullStr All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title_full_unstemmed All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title_short All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
title_sort all-trans retinoic acid (atra) regulates key genes in the rarg-top2b pathway and reduces anthracycline-induced cardiotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635745/
https://www.ncbi.nlm.nih.gov/pubmed/36331922
http://dx.doi.org/10.1371/journal.pone.0276541
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