Dihydrotestosterone Promotes Vascular Cell Adhesion Molecule-1 Expression in Male Human Endothelial Cells via a Nuclear Factor-κB-Dependent Pathway

There exists a striking gender difference in atherosclerotic vascular disease. For decades, estrogen was considered atheroprotective; however, an alternative is that androgen exposure in early life may predispose men to earlier atherosclerosis. We recently demonstrated that the potent androgen, dihydrotestosterone (DHT), enhanced the binding of monocytes to the endothelium, a key early event in atherosclerosis, via increased expression of vascular cell adhesion molecule-1 (VCAM-1). We now show that DHT mediates its effects on VCAM-1 expression at the promoter level through a novel androgen receptor (AR)/nuclear factor-κB (NF-κB) mechanism. Human umbilical vein endothelial cells were exposed to 4–400 nm DHT. DHT increased VCAM-1 mRNA in a dose- and time-dependent manner. The DHT effect could be blocked by the AR antagonist, hydroxyflutamide. DHT increased VCAM-1 promoter activity via NF-κB activation without affecting VCAM-1 mRNA stability. Using 5′ deletion analysis, it was determined that the NF-κB sites...