TY - JOUR
T1 - Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations
AU - Arimura, Takuro
AU - Onoue, Kenji
AU - Takahashi-Tanaka, Yumiko
AU - Ishikawa, Taisuke
AU - Kuwahara, Masayoshi
AU - Setou, Mitsutoshi
AU - Shigenobu, Shuji
AU - Yamaguchi, Katsushi
AU - Bertrand, Anne T.
AU - Machida, Noboru
AU - Takayama, Kazumi
AU - Fukusato, Masayuki
AU - Tanaka, Ryo
AU - Somekawa, Satoshi
AU - Nakano, Tomoya
AU - Yamane, Yoshihisa
AU - Kuba, Keiji
AU - Imai, Yumiko
AU - Saito, Yoshihiko
AU - Bonne, Gisèle
AU - Kimura, Akinori
N1 - Funding Information:
This work was supported in part by Grant-in-Aids from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant numbers 22390157, 23132507); grants for Japan–France collaboration research from the Japan Society for the Promotion of Science (JSPS) and the ‘Institut National de la Santé et de la Recherche Médicale’ (Inserm); a research grant for Intractable Disease from the Ministry of Health, Labour and Welfare, Japan (grantnumber 2010-119); a researchgrantfromthe ‘Association Franc¸aise contre les Myopathies’ (AFM) (grant number 15261); a Grant-in-Aid for SENTAN from the Japan Science and Technology Agency; and the Follow-up grants from the Tokyo Medical and Dental University. This work was also supported by Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University.
Publisher Copyright:
© The Author 2013.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Aims Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM. Methods and results A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples fromthe LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice. Conclusion These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.
AB - Aims Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM. Methods and results A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples fromthe LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice. Conclusion These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.
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U2 - 10.1093/cvr/cvt106
DO - 10.1093/cvr/cvt106
M3 - Article
C2 - 23631840
AN - SCOPUS:84888214014
SN - 0008-6363
VL - 99
SP - 382
EP - 394
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 3
ER -
