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

Discipline of Medicine (A.K.D., K.C.Y.M., D.S.C.), University of Sydney, Sydney, 2006 New South Wales, Australia; Heart Research Institute (M.A.S., S.N.), Camperdown, Sydney, 2050 New South Wales, Australia; Centre for Vascular Research (W.J.), Faculty of Medicine, University of New South Wales, Sydney, 2031 New South Wales, Australia; ANZAC Research Institute (D.J.H.), Concord, 2139 New South Wales, Australia; and Department of Cardiology (D.S.C.), Royal Prince Alfred Hospital, Sydney, 2050 New South Wales, Australia

Address all correspondence and requests for reprints to: Dr. Alison Death, Department of Medicine (D06), University of Sydney, Sydney, New South Wales 2006, Australia. E-mail: alison{at}med.usyd.edu.au.

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-B (NF-B) 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-B activation without affecting VCAM-1 mRNA stability. Using 5' deletion analysis, it was determined that the NF-B sites within the VCAM-1 promoter region were responsible for the DHT-mediated increase in VCAM-1 expression; however, coimmunoprecipitation studies suggested there is no direct interaction between AR and NF-B. Instead, DHT treatment decreased the level of the NF-B inhibitory protein. DHT did not affect VCAM-1 protein expression and monocyte adhesion when female endothelial cells were tested. AR expression was higher in male, relative to female, endothelial cells, associated with increased VCAM-1 levels. These findings highlight a novel AR/NF-B mediated mechanism for VCAM-1 expression and monocyte adhesion operating in male endothelial cells that may represent an important unrecognized mechanism for the male predisposition to atherosclerosis.