S-EPMC5859308 - Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription. - OmicsDI

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Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription.

ABSTRACT: 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. In this study, we identified the molecular mechanism by which androgen regulates ADTRP expression and 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 in a dose- and time-dependent manner, and the effect was abolished by three different androgen inhibitors, including pyrvinium pamoate, bicalutamide, and cyproterone acetate. Chromatin-immunoprecipitation showed that the androgen receptor bound to a half androgen response element (ARE, TGTTCT) located at +324bp from the ADTRP transcription start site. The ARE is required for concentration-dependent 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 rescued by ADTRP siRNA and exacerbated by overexpression of ADTRP and its downstream genes PIK3R3 and MIA3. These data suggest that one molecular mechanism by which androgen confers protection against CAD is stimulation of ADTRP expression.

SUBMITTER: Luo C

PROVIDER: S-EPMC5859308 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription.

Luo Chunyan C Pook Elisabeth E Tang Bo B Zhang Weiyi W Li Sisi S Leineweber Kirsten K Cheung Shing-Hu SH Chen Qiuyun Q Bechem Martin M Hu Jing-Shan JS Laux Volker V Wang Qing Kenneth QK

Biochimica et biophysica acta. Molecular basis of disease 20170620 9

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 unkno ...[more]

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