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Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model

Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor ag...

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Autores principales: Freiwan, Marah, Kovács, Mónika G., Kovács, Zsuzsanna Z. A., Szűcs, Gergő, Dinh, Hoa, Losonczi, Réka, Siska, Andrea, Kriston, András, Kovács, Ferenc, Horváth, Péter, Földesi, Imre, Cserni, Gábor, Dux, László, Csont, Tamás, Sárközy, Márta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877618/
https://www.ncbi.nlm.nih.gov/pubmed/35216317
http://dx.doi.org/10.3390/ijms23042201
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author Freiwan, Marah
Kovács, Mónika G.
Kovács, Zsuzsanna Z. A.
Szűcs, Gergő
Dinh, Hoa
Losonczi, Réka
Siska, Andrea
Kriston, András
Kovács, Ferenc
Horváth, Péter
Földesi, Imre
Cserni, Gábor
Dux, László
Csont, Tamás
Sárközy, Márta
author_facet Freiwan, Marah
Kovács, Mónika G.
Kovács, Zsuzsanna Z. A.
Szűcs, Gergő
Dinh, Hoa
Losonczi, Réka
Siska, Andrea
Kriston, András
Kovács, Ferenc
Horváth, Péter
Földesi, Imre
Cserni, Gábor
Dux, László
Csont, Tamás
Sárközy, Márta
author_sort Freiwan, Marah
collection PubMed
description Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.
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spelling pubmed-88776182022-02-26 Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model Freiwan, Marah Kovács, Mónika G. Kovács, Zsuzsanna Z. A. Szűcs, Gergő Dinh, Hoa Losonczi, Réka Siska, Andrea Kriston, András Kovács, Ferenc Horváth, Péter Földesi, Imre Cserni, Gábor Dux, László Csont, Tamás Sárközy, Márta Int J Mol Sci Article Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity. MDPI 2022-02-16 /pmc/articles/PMC8877618/ /pubmed/35216317 http://dx.doi.org/10.3390/ijms23042201 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Freiwan, Marah
Kovács, Mónika G.
Kovács, Zsuzsanna Z. A.
Szűcs, Gergő
Dinh, Hoa
Losonczi, Réka
Siska, Andrea
Kriston, András
Kovács, Ferenc
Horváth, Péter
Földesi, Imre
Cserni, Gábor
Dux, László
Csont, Tamás
Sárközy, Márta
Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title_full Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title_fullStr Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title_full_unstemmed Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title_short Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
title_sort investigation of the antiremodeling effects of losartan, mirabegron and their combination on the development of doxorubicin-induced chronic cardiotoxicity in a rat model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877618/
https://www.ncbi.nlm.nih.gov/pubmed/35216317
http://dx.doi.org/10.3390/ijms23042201
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