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 + 324 bp 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.

Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan

“…Testosterone administration improves endothelium-mediated vasodilation in some male animal models (34,36), and knockout of the AR gene increases atherosclerosis in male and female mice (19,59). Interesting recent data using EAhy926 endothelial cells identified specific androgen-stimulated genes intrinsic to the atheroprotective process (126). In contrast, and adding to the complexity, androgen administration can also blunt endothelium-mediated vasodilation in hypogonadal men by reducing NO availability (12), and testosterone exposure can worsen endothelial function (92) and hypertension in some animal models (155,208,251).…”

ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart

“…HeLa cells were plated in a 24-well plate and transfected with a 3TP-Luc reporter construct and pRL-TK with or without an ADAMTS16 expression plasmid using Fugene HD as described. [25][26][27][28] 30 hours later, cells were used for luciferase assays using the Dual Luciferase Reporter Assay System (Promega, Madison, WI, USA) as described by us previously. [25][26][27][28] Luciferase activities were normalized to Renilla luciferase activity.…”

Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1

“…Apoptosis assays were carried out with an Annexin V-FITC apoptosis analysis kit (keyGEN, BioTECH, China) using the Beckman Coulter Cytomics FC 500 as described (Luo et al 2017). Each experiment was repeated at least three times.…”