Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations
Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations
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DOI：
10.1093/cvr/cvt106
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发表时间：
2013-08-01
影响因子：
10.8
通讯作者：
Kimura, Akinori
中科院分区：
文献类型：
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作者：
Arimura, Takuro;Onoue, Kenji;Kimura, Akinori
扩张型心肌病（DCM）以心室扩张伴收缩功能障碍为特征，可能与lamina/C基因（LMNA）突变有关。在人类患者和携带纯合p.H222P突变（Lmna（H222 P/H222 P））的基因敲入小鼠模型中，LMNA连锁DCM在男性中均为重度。本研究通过对一个具有性别差异的DCM多重家系进行全外显子组分析，发现DCM连锁的LMNA突变p.R225X。对表达突变LMNA构建体的新生大鼠心肌细胞以及来自LMNA相关DCM患者和Lmna（H222 P/H222 P）小鼠的心脏样本的免疫组织化学分析表明雄激素受体（AR）及其共激活剂、血清反应因子和四个半LIM蛋白-2的核积聚。使用Lmna（H222 P/H222 P）小鼠在体内研究性激素在性别差异中的作用，其中雄性和雌性小鼠分别被阉割和卵巢切除，或用睾酮或AR拮抗剂处理。通过超声心动图检查、心脏组织学改变和基因/蛋白表达谱分析，证实睾丸激素参与了Lmna（H222 P/H222 P）小鼠的疾病进展和增强的心脏重构，这些观察结果表明AR核积聚与LMNA连锁DCM的性别差异有关。
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 (Lmna(H222P/H222P)). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM.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 from the LMNA-linked DCM patients and Lmna(H222P/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 Lmna(H222P/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 Lmna(H222P/H222P) mice.These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.