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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

View larger version (43K): [in a new window]   Figure 1 Effects of androgen exposure on macrophage gene expression. (A, B) Gene expression profiles in control- and androgen-treated male macrophages, respectively. There is enhanced expression of a large number of atherosclerosis-related genes (see Table 1). For example, the boxed areas containing lysosomal acid lipase (LAL) and acyl coA:cholesterol acyl transferase (ACAT) are enlarged and shown on the right. (C) Differential gene expression examined by reverse transcription-polymerase chain reaction (RT-PCR) shows the androgen-dependent gender-specific up-regulation of six atherosclerosis-associated genes: 1) ACAT; 2) LAL; 3) caveolin-2; 4) CD40; 5) tissue factor pathway inhibitor; and 6) vascular endothelial growth factor (VEGF)-165 receptor. In all genes studied by RT-PCR, androgen exposure produced up-regulation in gene expression in male-donor but not female-donor macrophages (p < 0.005 vs. control for all genes in male-donor cells as compared with p > 0.1 vs. control for all genes in female-donor cells). Open bars = controls; striped bars = 40 nmol/l dihydrotestosterone.

View larger version (17K): [in a new window]   Figure 2 Effects of androgen exposure on macrophage lipoprotein metabolism. (A) Androgen exposure increased the rate of lysosomal degradation of acetylated low-density lipoprotein (AcLDL) by male-donor monocyte-derived macrophages—a finding consistent with increased lysosomal acid lipase activity (p = 0.001 for dihydrotestosterone [DHT]-treated vs. control cells, at 20 h). (B) Androgen exposure had no effect on cell surface binding of 125I-AcLDL (p > 0.1 for androgen vs. control macrophages).