Unbound MEDLINE

Androgen receptor counteracts Doxorubicin-induced cardiotoxicity in male mice.

Abstract

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.

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  • Publisher Full Text
  • Authors

    Ikeda Y, Aihara K, Akaike M, Sato T, Ishikawa K, Ise T, Yagi S, Iwase T, Ueda Y, Yoshida S, Azuma H, Walsh K, Tamaki T, Kato S, Matsumoto T

    Source

    Molecular endocrinology (Baltimore, Md.) 24:7 2010 Jul pg 1338-48

    MeSH

    Androgens
    Animals
    Antineoplastic Agents
    Apoptosis
    Blotting, Western
    Cell Line
    Cell Survival
    DNA-Binding Proteins
    Doxorubicin
    Echocardiography
    High Mobility Group Proteins
    Immunoprecipitation
    In Situ Nick-End Labeling
    Male
    Mice
    Mice, Knockout
    Microscopy, Electron
    Myocardium
    Myocytes, Cardiac
    Oxidative Stress
    Phosphorylation
    Protein-Serine-Threonine Kinases
    Rats
    Receptors, Androgen
    Superoxides
    Testosterone
    Thiobarbituric Acid Reactive Substances
    Ventricular Function, Left

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    20501642