Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats

Ivanová, Monika; Dovinová, Ima; Okruhlicová, Ľudmila; Tribulová, N; Šimončíková, Petra; Barteková, Monika; Vlkovičová, Jana; Barančı́k, Miroslav

doi:10.1038/aps.2011.194

Cited by 50 publications

(46 citation statements)

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“…These results were confirmed with an apparent increase of caspase immunoreactivity of some muscle fibers in Doxo treated animals. This was confirmed by results of several investigators [5,[24][25][26] .…”

Section: Discussionsupporting

confidence: 87%

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The Possible Protective Role of Melatonin on Doxorubicin Induced Cardiomyopathy of Adult Male Albino Rats

Yassien

Elsaid

2017

Egyptian Journal of Histology

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Introduction: Doxorubicin is one of the major antitumor treatment. The essential limiting factor of using this drug is the production of cardiotoxicity. However, melatonin is a powerful antioxidant that may protect the heart. Aim: This study was aimed to study possible protective role of melatonin in adult male albino rats following doxorubicin administration Material and Method: In this study, 40 adult male albino rats were used. They were divided into four groups (10 rats for each): control group, Melatonin group, Doxorubicin group and Doxorubicin & Melatonin group. Heart specimens were obtained at the end and processed. Results: Light studies showed degenerative changes. Some fibers showed dark acidophilic cytoplasm and pyknotic nuclei. Apoptosis were detected where the nuclei varying from peripheral condensation of chromatin up to pyknosis, confirmed with positively caspase-3 activity. Dilatation of the vessels with mononuclear cellular infiltrations and deposited collagen fibers were seen. Ultrastructural examination showed disarrangement of the sarcomeres, disruption of microfilaments and Z-line, the number and size of mitochondria apparently increased, dilated SER and T tubules were also noticed. The presence of oval shaped cells (Telocyte) with thin long processes (Telopodes) were detected. Conclusion: From this study, it was concluded that, melatonin markedly suppressed cardiomyopathy induced by doxorubicin.

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Section: Discussionsupporting

confidence: 87%

“…production of reactive oxygen species (ROS) may be the cause of effects of DOX or through induction of nitric oxide synthases (NOS), leading to nitric oxide (NO) formation. It has been shown that, DOX treatment in vivo leads to cardiomyocytes apoptosis [4] , and increased levels of cleaved caspase-3 in DOX-treated animal's myocytes [5] .…”

Section: Introductionmentioning

confidence: 99%

The Possible Protective Role of Melatonin on Doxorubicin Induced Cardiomyopathy of Adult Male Albino Rats

Yassien

Elsaid

2017

Egyptian Journal of Histology

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“…Similarly, a previous study in rats with doxorubicin-induced cardiomyopathy did not document the active forms of both MMP 2 and 9, while pro-MMM 2 was also identified (Ivanová et al 2012). Inflammatory mediators activate neutrophils which, in turn, cause the release of MMP 9 from their granules (Sternlicht & Werb 2001).…”

Section: Discussionmentioning

confidence: 71%

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy

et al. 2018

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RESUMO.-[Metaloproteinases de matriz 2 e 9 em coelhos com cardiomiopatia induzida pela doxorrubicina.] Alguns estudos já demonstraram o papel exercido pelas metaloproteinases de matriz e seus inibidores na cardiotoxicidade promovida pela doxorrubicina. Assim, este estudo teve como objetivo investigar o comportamento das MMPs 2 e 9 plasmáticas e miocárdicas em coelhos com cardiomiopatia induzida pela doxorrubicina, buscando determinar se há correlação entre a atividade dessas colagenases e o remodelamento cardíaco. A cardiomiopatia foi induzida pela doxorrubicina aplicada por via intravenosa duas vezes por semana ao longo de seis semanas consecutivas. A atividade plasmática das MMPs e o ecocardiograma foram avaliados no momento basal e aos 15 e 45 dias após a primeira aplicação da doxorrubicina. A atividade miocárdica dessas enzimas foi quantificada em apenas nove coelhos aos 45 dias e os resultados comparados Some studies have shown the role played by matrix metalloproteinases and their inhibitors in doxorubicin cardiotoxicity. In this study, we sought to investigate how plasma and myocardial MMP 2 and 9 perform in rabbits with doxorubicin-induced cardiomyopathy, searching for a correlation between the activity of these collagenases and cardiac remodeling. Cardiomyopathy was induced by doxorubicin given intravenously twice a week for six consecutive weeks. Plasma MMP activity and the echocardiogram were assessed at baseline, and at 15 and 45 days after first injection of doxorubicin. The myocardial activity of these enzymes was solely evaluated in nine rabbits at 45 days, and results were compared with nine healthy controls. We only identified the full-length forms of both MMP 2 and 9 throughout the study. The plasma pro-MMP 2 reduced along the deterioration of cardiac function, while the pro-MMP 9 increased significantly at T45 as compared to baseline and T15. A negative significant correlation was found to exist between the plasma activity of pro-MMP 2 and mitral E-to-mitral septal annular early diastolic velocity ratio, which is an estimate of mean left atrial pressure and congestion. Only pro-MMP 2 was found in myocardial samples, and mean activity of such enzyme was statistically lower than that recorded for healthy controls. Although no active form was documented for either collagenase, the duration of the treatment with doxorubicin played a role in the alteration of plasma pro-forms activity. However, these changes could not be associated with most echocardiographic parameters that are supportive of cardiac remodeling. Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy com outros nove controles saudáveis. Foram identificadas apenas as formas inativas das MMPs 2 e 9 durante todo o estudo. A pro-MMP 2 plasmática reduziu à medida que a função cardiaca se deteriorou, enquanto a pro-MMP 9 aumentou significativamente em T45 quando comparada aos momentos basal e T15. Houve correlação negativa significativa entre a atividade plasmática da pro-MMP 2 e a relação entre E mitral e a ...

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“…Embora inicialmente fosse esperada imunomarcação aumentada de MMP2 nos grupos tratados com DOX, já que o estresse oxidativo pode ativar MMP e que TIMP2 pode ativar MMP2 (Bourboulia & Stetler-Stevenson 2010), Ivanová et al (2012), ao estudar ratos com cardiomiopatia induzida por DOX, encontraram aumento na atividade miocárdica da pro--MMP2 apenas oito semanas após a indução, quando havia acumulado a dose de 15mg/kg. Na presente pesquisa, apesar de a dose total acumulada ter sido 8 mg/kg, inferior à dose acumulada no citado estudo, acredita-se que o fator tempo possua grande influência na expressão dessas proteínas, fato também relatado por Ivanová et al (2012).…”

Section: Discussionunclassified

“…Na presente pesquisa, apesar de a dose total acumulada ter sido 8 mg/kg, inferior à dose acumulada no citado estudo, acredita-se que o fator tempo possua grande influência na expressão dessas proteínas, fato também relatado por Ivanová et al (2012). Nesse sentido, experimentos têm sido realizados buscando estabelecer curvas de expressão dessas proteínas, correlacionando-as com o tempo pós-aplicação da DOX.…”

Section: Discussionunclassified

Ação do extrato etanólico da casca do pequi (Caryocar brasiliense) na cardiotoxicidade crônica induzida por doxorrubicina em ratos

et al. 2017

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ABSTRACT.-Moura L.R., Orpinelli S.R.T., Sousa J.H., Faleiro M.B.R., Conceição E. Goiânia, Doxorubicin (DOX) is a chemotherapic drug used in the treatment of malignancies, but has the cardiotoxicity as collateral effect. The objective of this study was to evaluate the action of pequi shell etanolic extract (Caryocar brasiliense) (PSEE) through morphological evaluation (macroscopic, microscopic and ultramicroscopic), and to evaluate the expression of metalloproteinases (MMP2 and MMP9) and its tissue inhibitors (TIMP1 and TIMP2) in the myocardium of rats with chronic cardiotoxicity by DOX and treated or not with PSEE. The experiment lasted three months and 30 Wistar rats were divided into six groups of five animals. G1 and G2 received 300mg/kg and 600mg/kg of PSEE, respectively, as pretreatment, by gavage for seven days and continued treatment for 21 days of application of DOX. In G1, G2, G3, G4 and GC, cardiotoxicity was induced with weekly applications of 2mg/kg DOX, intraperitoneally, totaling four applications (8 mg/kg), and in the Sham group (GS) 1ml of saline solution was applied. G3 animals received daily 300mg/ kg of PSEE, and G4, 600mg/kg, by gavage, for 21 days of application of DOX. The GC and GS received 1ml of water daily by gavage also. After the completion of the application, the animals were kept for two months, with three months of experiment. Macroscopic evaluation was performed after 90 days, at which time samples were taken for analysis in electron microscopy, histopathology and immunohistochemistry. At necropsy, ascites was observed in animals that received DOX. There was a low mortality rate (3.33%), being one mouse that developed false road pneumonia. There was no change in weights and measures of the rat hearts. At doses of 300 and 600mg/kg, the PSEE attenuates myocyte vacuolar degeneration. At a dose of 600mg/kg, PSEE reduces amount Anitschkow cells. There was no significant result on the immunostaining of MMP, but considering their inhibitors (TIMP) there was a greater immunostaining of TIMP2 in GC, the group that received only DOX. It was concluded that PSEE is effective in minimizing effects of chronic cardiotoxicity induced by DOX in the myocardium of rats, whereas at doses of 300 and 600mg/ 1 Recebido em 13 de abril de 2016.Aceito para publicação em 12 de setembro de 2016.

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Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats

Cited by 50 publications

References 31 publications

The Possible Protective Role of Melatonin on Doxorubicin Induced Cardiomyopathy of Adult Male Albino Rats

The Possible Protective Role of Melatonin on Doxorubicin Induced Cardiomyopathy of Adult Male Albino Rats

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy

Ação do extrato etanólico da casca do pequi (Caryocar brasiliense) na cardiotoxicidade crônica induzida por doxorrubicina em ratos

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