Abstract 409: Androgen Inhibits Key Atherosclerotic Processes by Directly Activating ADTRP Transcription
Abstract 409: Androgen Inhibits Key Atherosclerotic Processes by Directly Activating ADTRP Transcription
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发表时间：
2017-05
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通讯作者：
Qiuyun Chen;Chunyan Luo;K. Leineweber;Bo Tang;Weiyi Zhang;Sisi Li;E. Pook;S. Cheung;M. Bechem;Jing-Shan Hu;V. Laux;Q. Wang
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作者：
Qiuyun Chen;Chunyan Luo;K. Leineweber;Bo Tang;Weiyi Zhang;Sisi Li;E. Pook;S. Cheung;M. Bechem;Jing-Shan Hu;V. Laux;Q. Wang
低雄激素水平与冠状动脉疾病(CAD)、血栓形成和心肌梗死(MI)的风险增加相关，这表明雄激素具有保护作用。然而，人们对其潜在的分子机制知之甚少。我们的全基因组关联研究发现，编码雄激素依赖性TFPI调节蛋白的ADTRP基因是冠心病和心肌梗死的易感基因。ADTRP的表达水平受雄激素的调节，但其分子机制尚不清楚。在这里，我们验证了雄激素通过激活ADTRP表达在心血管疾病中发挥保护作用的假设。用ADTRP启动子荧光素酶报告基因进行的荧光素酶分析表明，雄激素调节ADTRP的转录。染色质免疫沉淀显示，雄激素受体与雄激素反应元件(ARE)结合在距ADTRP转录起始点+324bp处。ARE是ADTRP转录激活所必需的。雄激素抑制HL-60单核细胞与EAhy926内皮细胞(ECs)的黏附和跨EC层的迁移，而ADTRP siRNA可抑制这一作用，而ADTRP过表达则可增强其作用。这些数据表明，雄激素对冠心病提供保护的一个分子机制是刺激ADTRP的表达。
Low androgen levels are associated with an increased risk of coronary artery disease (CAD), thrombosis and myocardial infarction (MI), suggesting that androgen has a protective role. However, little is known about the underlying molecular mechanism. Our genome-wide association study identified the ADTRP gene encoding the androgen-dependent TFPI regulating protein as a susceptibility gene for CAD and MI. The expression level of ADTRP was regulated by androgen, but the molecular mechanism is unknown. Here, we tested the hypothesis that androgen plays a protective role in cardiovascular disease by activating ADTRP expression. Luciferase assays with an ADTRP promoter luciferase reporter revealed that androgen regulated ADTRP transcription. Chromatin-immunoprecipitation showed that the androgen receptor bound to a half androgen response element (ARE) located at +324bp from the ADTRP transcription start site. The ARE is required for the transcriptional activation of ADTRP . HL-60 monocyte adhesion to EAhy926 endothelial cells (ECs) and transmigration across the EC layer, the two processes critical to development of CAD and MI, were inhibited by androgen, but the effect was reduced by ADTRP siRNA and enhanced by overexpression of ADTRP . These data suggest that one molecular mechanism by which androgen confers protection against CAD is stimulation of ADTRP expression.