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EXPEDITED REVIEW

Androgens Up-Regulate Atherosclerosis-Related Genes in Macrophages From Males But Not Females

Molecular Insights Into Gender Differences in Atherosclerosis

Martin K. C. Ng, MBBS, FRACP^*, Carmel M. Quinn, DPhil, Jane A. McCrohon, MBBS, PhD, FRACP, Shirley Nakhla, BSc, Wendy Jessup, PhD, David J. Handelsman, MBBS, PhD, FRACP, David S. Celermajer, MBBS, PhD, FRACP^*||,* and Alison K. Death, PhD^||

^* 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
ANZAC Research Institute, Sydney, Australia
^|| Department of Medicine, University of Sydney, Sydney, Australia

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

OBJECTIVES: This study investigated the effects of androgens on gene expression in male- and female-donor macrophages.

BACKGROUND: Men have more severe coronary disease than women. Androgen exposure increases foam cell formation in male but not female macrophages, and male macrophages express >4-fold more androgen receptor messenger ribonucleic acid than female macrophages. Therefore, androgen exposure may have gender-specific and potentially pro-atherogenic effects in macrophages.

METHODS: Utilizing complementary deoxyribonucleic acid arrays, we studied the effects of a pure androgen (dihydrotestosterone, 40 nmol/l) on human monocyte-derived macrophages from healthy male and female donors (n = 4 hybridizations; 2 men, 2 women). Differential expression of atherosclerosis-related genes was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in five male and five female donors. Functional corroboration of foam cell formation-related findings was undertaken by experiments using ¹²⁵I-acetylated low-density lipoprotein (AcLDL).

RESULTS: In male macrophages, androgen treatment produced differential up-regulation of 27 genes concentrated in five functional classes: 1) lipoprotein processing; 2) cell-surface adhesion; 3) extracellular signaling; 4) coagulation and fibrinolysis; and 5) transport protein genes. By contrast, none of 588 genes were up-regulated in female macrophages. By RT-PCR, we confirmed the gender-specific up-regulation of six of these atherosclerosis-related genes: acyl coenzyme A:cholesterol acyl transferase I, lysosomal acid lipase (LAL), caveolin-2, CD40, vascular endothelial growth factor-165 receptor, and tissue factor pathway inhibitor. Functionally, androgen-treated male macrophages showed increased rates of lysosomal AcLDL degradation, by 45% to 75% after 15 to 20 h of ¹²⁵I-AcLDL incubation (p = 0.001), consistent with increased LAL activity.

CONCLUSIONS: Androgens increase expression of atherosclerosis-related genes in male but not female macrophages, with functional consequences. These findings may contribute to the male predisposition to atherosclerosis.

Abbreviations and Acronyms   ACAT = acyl coenzyme A:cholesterol acyl transferase I   AcLDL = acetylated low-density lipoprotein   AR = androgen receptor   cDNA = complementary deoxyribonucleic acid   DHT = dihydrotestosterone   LAL = lysosomal acid lipase   MDM = monocyte-derived macrophage   RNA = ribonucleic acid   RT-PCR = reverse transcription-polymerase chain reaction   TFPI = tissue factor pathway inhibitor   VEGF = vascular endothelial growth factor

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