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CLINICAL RESEARCH: ATHEROSCLEROSIS

Dehydroepiandrosterone, an adrenalandrogen, increases human foam cell formation

a potentially pro-atherogenic effect

Martin K. C. Ng, MBBS, FRACP^*, Shirley Nakhla, BSc, Anna Baoutina, PhD, Wendy Jessup, PhD, David J. Handelsman, MBBS, PhD, FRACP^|| and David S. Celermajer, MBBS, PhD, FRACP^*,*

^* Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
Heart Research Institute, Sydney, Australia
Centre for Vascular Research, University of New South Wales, Sydney, Australia
Department of Andrology, Concord Hospital, Sydney, Australia
^|| ANZAC Research Institute, Sydney, Australia

Manuscript received February 27, 2003; revised manuscript received June 22, 2003, accepted July 6, 2003.

^* Reprint requests and correspondence: Dr. David S. Celermajer, Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, Sydney, N.S.W. 2050, Australia.
david.celermajer{at}email.cs.nsw.gov.au

OBJECTIVES: We 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.

BACKGROUND: In 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.

METHODS: Regarding 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.

RESULTS: DHEA 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).

CONCLUSIONS: DHEA 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.

Abbreviations and Acronyms   ACAT = acyl coenzyme A:cholesterol acyltransferase I   CE = cholesteryl ester   DHEA = dehydroepiandrosterone   DHEAS = dehydroepiandrosterone sulfate   HCAEC = human coronary artery endothelial cell   HF = hydroxyflutamide   HUVEC = human umbilical vein endothelial cell   ICAM-1 = intercellular adhesion molecule-1   IL-1-beta = interleukin-1-beta   LAL = lysosomal acid lipase   LDL = low-density lipoprotein   MDM = monocyte-derived macrophage   PBS = phosphate-buffered saline   RT-PCR = reverse-transcription polymerase chain reaction   VCAM-1 = vascular cell adhesion molecule-1

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