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.

Links

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

Institution

Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, Tokushima 770-8503, Japan.

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