title: 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.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, Tokushima 770-8503, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Kazue
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ise
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Azuma
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D006609:High Mobility Group Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D011944:Receptors, Androgen; C081930:Tfam protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D013739:Testosterone; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases