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Research ArticleToxicology

Chronic Anthracycline Cardiotoxicity: Molecular and Functional Analysis with Focus on Nuclear Factor Erythroid 2-Related Factor 2 and Mitochondrial Biogenesis Pathways

Eduard Jirkovský, Olga Popelová, Pavla Křiváková-Staňková, Anna Vávrová, Miloš Hroch, Pavlína Hašková, Eva Brčáková-Doleželová, Stanislav Mičuda, Michaela Adamcová, Tomáš Šimůnek, Zuzana Červinková, Vladimír Geršl and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 468-478; DOI: https://doi.org/10.1124/jpet.112.198358
Eduard Jirkovský
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Olga Popelová
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Pavla Křiváková-Staňková
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Anna Vávrová
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Miloš Hroch
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Pavlína Hašková
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Eva Brčáková-Doleželová
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Stanislav Mičuda
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Michaela Adamcová
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Tomáš Šimůnek
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Zuzana Červinková
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Vladimír Geršl
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Martin Štěrba
Departments of Pharmacology (E.J., O.P., M.H., E.B.-D., S.M., V.G., M.S.), Physiology (P.K.-S., M.A., Z.C.), and Medical Biochemistry (M.H.), Faculty of Medicine in Hradec Králové, and Departments of Biochemical Sciences (A.V., P.H., T.S.) and Biological and Medical Sciences (E.B.-D.), Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
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Abstract

Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow-up were analyzed with special emphasis on nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks), and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow-up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although marked perturbations in mitochondrial functions were found, no induction of PGC1α-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved.

Footnotes

  • This study was supported by the Czech Science Foundation [Grant 305/09/0416]; Charles University [Grant SVV 264901/2012 and the program PRVOUK P37/5].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.198358.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ANT
    anthracycline
    ANOVA
    analysis of variance
    ARE
    antioxidant response element
    COX
    cytochrome c oxidase
    CTR
    control
    CuZnSOD
    copper zinc superoxide dismutase
    DAU
    daunorubicin
    DTT
    dithiothreitol
    FS
    fractional shortening
    FU
    follow-up
    GCLC
    glutamate-cysteine ligase catalytic subunit
    GPx
    glutathione peroxidase
    GR
    glutathione reductase
    GSH
    reduced glutathione
    GSSG
    oxidized glutathione
    GST
    glutathione transferase
    HO1
    heme oxygenase 1
    HPLC
    high-performance liquid chromatography
    LMV
    last measured value
    LV
    left ventricular
    LVEDD
    LV end-diastolic diameter
    MDA
    malondialdehyde
    MnSOD
    manganese superoxide dismutase
    mtDNA
    mitochondrial DNA
    nDNA
    nuclear DNA
    NQO1
    NAD(P)H dehydrogenase [quinone] 1
    NRF1
    nuclear respiratory factor 1
    Nrf2
    nuclear factor erythroid 2-related factor 2
    PCR
    polymerase chain reaction
    qPCR
    quantitative PCR
    PGC1α
    peroxisome proliferator-activated receptor γ coactivator 1α
    ROS
    reactive oxygen species
    smtCK
    sarcomeric mitochondrial creatine kinase
    TFAM
    mitochondrial transcription factor A.

  • Received July 11, 2012.
  • Accepted August 21, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleToxicology

Chronic Anthracycline Cardiotoxicity, Nrf2, and PGC1α

Eduard Jirkovský, Olga Popelová, Pavla Křiváková-Staňková, Anna Vávrová, Miloš Hroch, Pavlína Hašková, Eva Brčáková-Doleželová, Stanislav Mičuda, Michaela Adamcová, Tomáš Šimůnek, Zuzana Červinková, Vladimír Geršl and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 468-478; DOI: https://doi.org/10.1124/jpet.112.198358

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Research ArticleToxicology

Chronic Anthracycline Cardiotoxicity, Nrf2, and PGC1α

Eduard Jirkovský, Olga Popelová, Pavla Křiváková-Staňková, Anna Vávrová, Miloš Hroch, Pavlína Hašková, Eva Brčáková-Doleželová, Stanislav Mičuda, Michaela Adamcová, Tomáš Šimůnek, Zuzana Červinková, Vladimír Geršl and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 468-478; DOI: https://doi.org/10.1124/jpet.112.198358
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