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Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice

Sex is a salient risk factor in the development of doxorubicin-induced cardiotoxicity. Sex differences in the heart’s ability to respond to hypertrophic stimuli in doxorubicin-exposed animals have not been reported. We identified the sexual dimorphic effects of isoproterenol in mice pre-exposed to d...

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Autores principales: Agostinucci, Kevin, Grant, Marianne K. O., Melaku, Wongel, Nair, Chandini, Zordoky, Beshay N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058259/
https://www.ncbi.nlm.nih.gov/pubmed/36986490
http://dx.doi.org/10.3390/ph16030391
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author Agostinucci, Kevin
Grant, Marianne K. O.
Melaku, Wongel
Nair, Chandini
Zordoky, Beshay N.
author_facet Agostinucci, Kevin
Grant, Marianne K. O.
Melaku, Wongel
Nair, Chandini
Zordoky, Beshay N.
author_sort Agostinucci, Kevin
collection PubMed
description Sex is a salient risk factor in the development of doxorubicin-induced cardiotoxicity. Sex differences in the heart’s ability to respond to hypertrophic stimuli in doxorubicin-exposed animals have not been reported. We identified the sexual dimorphic effects of isoproterenol in mice pre-exposed to doxorubicin. Male and female intact or gonadectomized C57BL/6N mice underwent five weekly intraperitoneal injections of 4 mg/kg doxorubicin followed by a five-week recovery period. Fourteen days of subcutaneous isoproterenol injections (10 mg/kg/day) were administered after the recovery period. Echocardiography was used to assess heart function one and five weeks after the last doxorubicin injection and on the fourteenth day of isoproterenol treatment. Thereafter, mice were euthanized, and the hearts were weighed and processed for histopathology and gene expression analysis. Doxorubicin did not produce overt cardiac dysfunction in male or female mice before starting isoproterenol treatment. The chronotropic response to a single isoproterenol injection was blunted by doxorubicin, but the inotropic response was maintained in both males and females. Pre-exposure to doxorubicin caused cardiac atrophy in both control and isoproterenol-treated male mice but not in female mice. Counterintuitively, pre-exposure to doxorubicin abrogated isoproterenol-induced cardiac fibrosis. However, there were no sex differences in the expression of markers of pathological hypertrophy, fibrosis, or inflammation. Gonadectomy did not reverse the sexually dimorphic effects of doxorubicin. Additionally, pre-exposure to doxorubicin abrogated the hypertrophic response to isoproterenol in castrated male mice but not in ovariectomized female mice. Therefore, pre-exposure to doxorubicin caused male-specific cardiac atrophy that persisted after isoproterenol treatment, which could not be prevented by gonadectomy.
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spelling pubmed-100582592023-03-30 Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice Agostinucci, Kevin Grant, Marianne K. O. Melaku, Wongel Nair, Chandini Zordoky, Beshay N. Pharmaceuticals (Basel) Article Sex is a salient risk factor in the development of doxorubicin-induced cardiotoxicity. Sex differences in the heart’s ability to respond to hypertrophic stimuli in doxorubicin-exposed animals have not been reported. We identified the sexual dimorphic effects of isoproterenol in mice pre-exposed to doxorubicin. Male and female intact or gonadectomized C57BL/6N mice underwent five weekly intraperitoneal injections of 4 mg/kg doxorubicin followed by a five-week recovery period. Fourteen days of subcutaneous isoproterenol injections (10 mg/kg/day) were administered after the recovery period. Echocardiography was used to assess heart function one and five weeks after the last doxorubicin injection and on the fourteenth day of isoproterenol treatment. Thereafter, mice were euthanized, and the hearts were weighed and processed for histopathology and gene expression analysis. Doxorubicin did not produce overt cardiac dysfunction in male or female mice before starting isoproterenol treatment. The chronotropic response to a single isoproterenol injection was blunted by doxorubicin, but the inotropic response was maintained in both males and females. Pre-exposure to doxorubicin caused cardiac atrophy in both control and isoproterenol-treated male mice but not in female mice. Counterintuitively, pre-exposure to doxorubicin abrogated isoproterenol-induced cardiac fibrosis. However, there were no sex differences in the expression of markers of pathological hypertrophy, fibrosis, or inflammation. Gonadectomy did not reverse the sexually dimorphic effects of doxorubicin. Additionally, pre-exposure to doxorubicin abrogated the hypertrophic response to isoproterenol in castrated male mice but not in ovariectomized female mice. Therefore, pre-exposure to doxorubicin caused male-specific cardiac atrophy that persisted after isoproterenol treatment, which could not be prevented by gonadectomy. MDPI 2023-03-04 /pmc/articles/PMC10058259/ /pubmed/36986490 http://dx.doi.org/10.3390/ph16030391 Text en © 2023 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
Agostinucci, Kevin
Grant, Marianne K. O.
Melaku, Wongel
Nair, Chandini
Zordoky, Beshay N.
Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title_full Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title_fullStr Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title_full_unstemmed Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title_short Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice
title_sort exposure to doxorubicin modulates the cardiac response to isoproterenol in male and female mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058259/
https://www.ncbi.nlm.nih.gov/pubmed/36986490
http://dx.doi.org/10.3390/ph16030391
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