Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations

Takuro Arimura, Kenji Onoue, Yumiko Takahashi-Tanaka, Taisuke Ishikawa, Masayoshi Kuwahara, Mitsutoshi Setou, Shuji Shigenobu, Katsushi Yamaguchi, Anne T. Bertrand, Noboru Machida, Kazumi Takayama, Masayuki Fukusato, Ryo Tanaka, Satoshi Somekawa, Tomoya Nakano, Yoshihisa Yamane, Keiji Kuba, Yumiko Imai, Yoshihiko Saito, Gisèle BonneAkinori Kimura

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)382-394
Number of pages13
JournalCardiovascular research
Volume99
Issue number3
DOIs
Publication statusPublished - Aug 1 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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