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J. Biol. Chem., Vol. 280, Issue 33, 29661-29666, August 19, 2005

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Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-induced Cardiac Fibrosis^*

Yasumasa Ikeda, Ken-ichi Aihara, Takashi Sato¶, Masashi Akaike, Masanori Yoshizumi||, Yuki Suzaki||, Yuki Izawa||, Mitsunori Fujimura, Shunji Hashizume, Midori Kato, Shusuke Yagi, Toshiaki Tamaki||, Hirotaka Kawano¶, Takahiro Matsumoto¶, Hiroyuki Azuma, Shigeaki Kato¶, and Toshio Matsumoto**

From the Department of Medicine and Bioregulatory Sciences and ^||Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, and the ^¶Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.

Received for publication, October 14, 2004 , and in revised form, June 1, 2005.

^* This work was supported in part by Grants-in-Aid for Scientific Research and a Grant for the 21st Century Center of Excellence Program from the Ministry of Education, Science, Sports and Culture of Japan, and a Grant for a Study Group on Aseptic Femoral Neck Necrosis from the Ministry of Health, Labor and Welfare of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1 and S2.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 81-88-633-7120; Fax: 81-88-633-7121; E-mail: toshimat{at}clin.med.tokushima-u.ac.jp.

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