Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | por |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/101008 https://doi.org/10.1093/toxsci/kfz026 |
Resumo: | Doxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities. |
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Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Ratsanimal study; cardiotoxicity; doxorubicin; feature correlation analysis; mitochondrial permeability transition; principal component analysisAnimalsAntibiotics, AntineoplasticCalciumCardiotoxicityCell RespirationDoxorubicinElectron Transport Chain Complex ProteinsHeart DiseasesHydrogen PeroxideMaleMitochondria, HeartMyocytes, CardiacRats, WistarTime FactorsDoxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities.2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/101008http://hdl.handle.net/10316/101008https://doi.org/10.1093/toxsci/kfz026por1096-60801096-0929Pereira, Gonçalo CastroPereira, Susana P.Pereira, Francisco B.Lourenço, Nuno António MarquesLumini, José APereira, Cláudia V.Bjork, James A.Magalhães, JoséAscensão, AntónioWieckowski, Mariusz R.Moreno, António JWallace, Kendall B.Oliveira, Paulo Jinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-11-07T09:18:18Zoai:estudogeral.uc.pt:10316/101008Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:18:16.341768Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
title |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
spellingShingle |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats Pereira, Gonçalo Castro animal study; cardiotoxicity; doxorubicin; feature correlation analysis; mitochondrial permeability transition; principal component analysis Animals Antibiotics, Antineoplastic Calcium Cardiotoxicity Cell Respiration Doxorubicin Electron Transport Chain Complex Proteins Heart Diseases Hydrogen Peroxide Male Mitochondria, Heart Myocytes, Cardiac Rats, Wistar Time Factors |
title_short |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
title_full |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
title_fullStr |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
title_full_unstemmed |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
title_sort |
Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats |
author |
Pereira, Gonçalo Castro |
author_facet |
Pereira, Gonçalo Castro Pereira, Susana P. Pereira, Francisco B. Lourenço, Nuno António Marques Lumini, José A Pereira, Cláudia V. Bjork, James A. Magalhães, José Ascensão, António Wieckowski, Mariusz R. Moreno, António J Wallace, Kendall B. Oliveira, Paulo J |
author_role |
author |
author2 |
Pereira, Susana P. Pereira, Francisco B. Lourenço, Nuno António Marques Lumini, José A Pereira, Cláudia V. Bjork, James A. Magalhães, José Ascensão, António Wieckowski, Mariusz R. Moreno, António J Wallace, Kendall B. Oliveira, Paulo J |
author2_role |
author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Pereira, Gonçalo Castro Pereira, Susana P. Pereira, Francisco B. Lourenço, Nuno António Marques Lumini, José A Pereira, Cláudia V. Bjork, James A. Magalhães, José Ascensão, António Wieckowski, Mariusz R. Moreno, António J Wallace, Kendall B. Oliveira, Paulo J |
dc.subject.por.fl_str_mv |
animal study; cardiotoxicity; doxorubicin; feature correlation analysis; mitochondrial permeability transition; principal component analysis Animals Antibiotics, Antineoplastic Calcium Cardiotoxicity Cell Respiration Doxorubicin Electron Transport Chain Complex Proteins Heart Diseases Hydrogen Peroxide Male Mitochondria, Heart Myocytes, Cardiac Rats, Wistar Time Factors |
topic |
animal study; cardiotoxicity; doxorubicin; feature correlation analysis; mitochondrial permeability transition; principal component analysis Animals Antibiotics, Antineoplastic Calcium Cardiotoxicity Cell Respiration Doxorubicin Electron Transport Chain Complex Proteins Heart Diseases Hydrogen Peroxide Male Mitochondria, Heart Myocytes, Cardiac Rats, Wistar Time Factors |
description |
Doxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/101008 http://hdl.handle.net/10316/101008 https://doi.org/10.1093/toxsci/kfz026 |
url |
http://hdl.handle.net/10316/101008 https://doi.org/10.1093/toxsci/kfz026 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.none.fl_str_mv |
1096-6080 1096-0929 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799134077696081920 |