Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification
Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification
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DOI：
10.1038/srep24807
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发表时间：
2016-04-20
影响因子：
4.6
通讯作者：
MacRae, Vicky E.
中科院分区：
文献类型：
--
作者：
Zhu, Dongxing;Hadoke, Patrick W. F.;MacRae, Vicky E.
血管钙化有力地预测了心血管疾病的死亡率和发病率。与同龄女性相比，男性患心血管疾病的风险更大。这些性别差异表明性激素的影响。睾酮是男性中最主要和最公认的雄激素。因此，我们提出了外源性雄激素治疗诱导血管钙化的假设。免疫组化分析显示，雄激素受体（AR）的表达在钙化的人股动脉组织和钙化的人瓣膜的中膜。此外，体外研究显示，睾酮或二氢睾酮（DHT）治疗9天后，磷酸盐（Pi）诱导的小鼠血管平滑肌细胞（VSMC）钙化增加。睾酮和双氢睾酮处理增加组织非特异性碱性磷酸酶（Alpl）mRNA的表达。与WT相比，VSMC特异性AR消融（SM-ARKO）VSMC中睾酮诱导的钙化减弱。与这些数据一致，SM-ARKO VSMC显示Osterix mRNA表达降低。然而，有趣的是，观察到Alpl的反直觉增加。这些新的数据表明，雄激素通过AR在诱导血管钙化中发挥作用。雄激素信号传导可能代表临床干预的新的潜在治疗靶点。
Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.