Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Bunkyo-Ku, Tokyo 113-8510, Japan.
Cardiovasc Res. 2013 Aug 1;99(3):382-94. doi: 10.1093/cvr/cvt106. Epub 2013 Apr 30.
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.
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 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.
These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.
扩张型心肌病（DCM）的特征是心室扩张伴收缩功能障碍，这可能是由层粘连蛋白/C 基因（LMNA）的突变引起的。在携带纯合 p.H222P 突变（LmnaH222P/H222P）的人类患者和敲入小鼠模型中，LMNA 相关的 DCM 在男性中较为严重。本研究旨在探讨 LMNA 相关 DCM 性别差异的分子机制。
对一个表现出性别差异的 DCM 多态性家族进行全外显子分析，发现了一个与 DCM 相关的 LMNA 突变，p.R225X。表达突变 LMNA 构建体的新生大鼠心肌细胞和来自 LMNA 相关 DCM 患者和 LmnaH222P/H222P 小鼠的心脏样本的免疫组织化学分析表明，雄激素受体（AR）及其共激活因子血清反应因子和四半LIM 蛋白-2 发生核内聚集。使用 LmnaH222P/H222P 小鼠体内研究性激素在性别差异中的作用，对雄性和雌性小鼠分别进行去势和卵巢切除术，或用睾丸激素或 AR 拮抗剂进行治疗。通过超声心动图检查小鼠，然后分析心脏的组织学变化和基因/蛋白表达谱，证实了睾丸激素在疾病进展中的作用以及在 LmnaH222P/H222P 小鼠中增强的心脏重塑作用。
这些观察结果表明，AR 的核内聚集与 LMNA 相关 DCM 的性别差异有关。
