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Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway.

Abstract

Metallothionein (MT) has been shown to inhibit cardiac oxidative stress and protect against the cardiotoxicity induced by doxorubicin (DOX), a potent and widely used chemotherapeutic agent. However, the mechanism of MT׳s protective action against DOX still remains obscure. Mitochondrial biogenesis impairment has been implicated to play an important role in the etiology and progression of DOX-induced cardiotoxicity. Increasing evidence indicates an intimate link between MT-mediated cardioprotection and mitochondrial biogenesis. This study was aimed to explore the possible contribution of mitochondrial biogenesis in MT׳s cardioprotective action against DOX. Adult male MT-I/II-null (MT(-/-)) and wild-type (MT(+/+)) mice were given a single dose of DOX intraperitoneally. Our results revealed that MT deficiency significantly sensitized mice to DOX-induced cardiac dysfunction, ultrastructural alterations, and mortality. DOX disrupted cardiac mitochondrial biogenesis indicated by mitochondrial DNA copy number and decreased mitochondrial number, and these effects were greater in MT(-/-) mice. Basal MT effectively protected against DOX-induced inhibition on the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, and its downstream factors including mitochondrial transcription factor A. Moreover, MT was found to preserve the protein expression of manganese superoxide dismutase, a transcriptional target of PGC-1α. in vitro study showed that MT absence augmented DOX-induced increase of mitochondrial superoxide production in primary cultured cardiomyocytes. These findings suggest that MT׳s cardioprotection against DOX is mediated, at least in part, by preservation of mitochondrial biogenesis involving PGC-1α pathway.

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  • Authors+Show Affiliations

    ,

    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

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    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

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    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

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    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

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    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

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    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.

    Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China. Electronic address: pengsq@hotmail.com.

    Source

    European journal of pharmacology 737: 2014 Aug 15 pg 117-24

    MeSH

    Animals
    DNA-Binding Proteins
    Doxorubicin
    Gene Knockout Techniques
    Heart
    High Mobility Group Proteins
    Male
    Metallothionein
    Mice
    Mitochondria, Heart
    Oxidative Stress
    Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
    Transcription Factors

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24858368

    Citation

    Guo, Jiabin, et al. "Cardioprotection Against Doxorubicin By Metallothionein Is Associated With Preservation of Mitochondrial Biogenesis Involving PGC-1α Pathway." European Journal of Pharmacology, vol. 737, 2014, pp. 117-24.
    Guo J, Guo Q, Fang H, et al. Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway. Eur J Pharmacol. 2014;737:117-24.
    Guo, J., Guo, Q., Fang, H., Lei, L., Zhang, T., Zhao, J., & Peng, S. (2014). Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway. European Journal of Pharmacology, 737, pp. 117-24. doi:10.1016/j.ejphar.2014.05.017.
    Guo J, et al. Cardioprotection Against Doxorubicin By Metallothionein Is Associated With Preservation of Mitochondrial Biogenesis Involving PGC-1α Pathway. Eur J Pharmacol. 2014 Aug 15;737:117-24. PubMed PMID: 24858368.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway. AU - Guo,Jiabin, AU - Guo,Qian, AU - Fang,Haiqing, AU - Lei,Lei, AU - Zhang,Tingfen, AU - Zhao,Jun, AU - Peng,Shuangqing, Y1 - 2014/05/22/ PY - 2014/03/20/received PY - 2014/05/08/revised PY - 2014/05/14/accepted PY - 2014/5/27/entrez PY - 2014/5/27/pubmed PY - 2015/2/14/medline KW - Cardiotoxicity KW - Doxorubicin KW - Doxorubicin (PubChem CID: 23214928) KW - Metallothionein KW - Mitochondrial biogenesis KW - PGC-1α SP - 117 EP - 24 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 737 N2 - Metallothionein (MT) has been shown to inhibit cardiac oxidative stress and protect against the cardiotoxicity induced by doxorubicin (DOX), a potent and widely used chemotherapeutic agent. However, the mechanism of MT׳s protective action against DOX still remains obscure. Mitochondrial biogenesis impairment has been implicated to play an important role in the etiology and progression of DOX-induced cardiotoxicity. Increasing evidence indicates an intimate link between MT-mediated cardioprotection and mitochondrial biogenesis. This study was aimed to explore the possible contribution of mitochondrial biogenesis in MT׳s cardioprotective action against DOX. Adult male MT-I/II-null (MT(-/-)) and wild-type (MT(+/+)) mice were given a single dose of DOX intraperitoneally. Our results revealed that MT deficiency significantly sensitized mice to DOX-induced cardiac dysfunction, ultrastructural alterations, and mortality. DOX disrupted cardiac mitochondrial biogenesis indicated by mitochondrial DNA copy number and decreased mitochondrial number, and these effects were greater in MT(-/-) mice. Basal MT effectively protected against DOX-induced inhibition on the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, and its downstream factors including mitochondrial transcription factor A. Moreover, MT was found to preserve the protein expression of manganese superoxide dismutase, a transcriptional target of PGC-1α. in vitro study showed that MT absence augmented DOX-induced increase of mitochondrial superoxide production in primary cultured cardiomyocytes. These findings suggest that MT׳s cardioprotection against DOX is mediated, at least in part, by preservation of mitochondrial biogenesis involving PGC-1α pathway. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24858368/Cardioprotection_against_doxorubicin_by_metallothionein_Is_associated_with_preservation_of_mitochondrial_biogenesis_involving_PGC_1α_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(14)00379-3 DB - PRIME DP - Unbound Medicine ER -