Dehydroepiandrosterone, an adrenalandrogen, increases human foam cell formation: a potentially pro-atherogenic effect

Abstract

ObjectivesWe studied the effects of dehydroepiandrosterone (DHEA), an abundant adrenal androgen, on two key early events of atherogenesis: 1) human monocyte adhesion to vascular endothelium, and 2) human foam cell formation. BackgroundIn the U.S., where DHEA is available without prescription, there has recently been a rapid increase in unsupervised self-administration of DHEA. The vascular biologic effects of DHEA are largely unknown, however. MethodsRegarding adhesion, human umbilical vein endothelial cells (HUVECs), exposed to either DHEA (42 or 420 nmol/l) or control, were incubated with human monocytes, and adhesion was measured by hemocytometry. Surface expression of endothelial cell adhesion molecules was measured by ELISA. Regarding foam cell formation, studies of lipid loading were performed on macrophages treated with DHEA or control and/or the androgen receptor antagonist hydroxyflutamide (HF) (4 μmol/l). Intracellular cholesterol and cholesteryl esters (CE) were quantified by high-performance liquid chromatography. Expression of foam cell formation-related genes was measured by reverse-transcription polymerase chain reaction. ResultsDHEA produced a dose-dependent receptor-mediated increase in the male macrophage CE content (up to 120 ± 4% of control values, p = 0.015). DHEA upregulated messenger ribonucleic acid expression of the lipoprotein-processing enzymes acyl coenzyme A:cholesterol acyltransferase I and lysosomal acid lipase by 3.4- and 5.3-fold, respectively (p < 0.05 vs. control), but had no effect on scavenger receptor expression (p > 0.2). There was no significant effect of DHEA on monocyte–endothelial adhesion (<10% change in values, p = 0.56) or endothelial cell expression of cell adhesion molecules (p > 0.1). ConclusionsDHEA increases human macrophage foam cell formation, a potentially pro-atherogenic effect. This effect appears to be mediated via the androgen receptor and involves the upregulation of lipoprotein-processing enzymes.