Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis.
OBJECTIVE
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 (125)I-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 (125)I-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.
Ng
Martin K C
MK
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
Quinn
Carmel M
CM
McCrohon
Jane A
JA
Nakhla
Shirley
S
Jessup
Wendy
W
Handelsman
David J
DJ
Celermajer
David S
DS
Death
Alison K
AK
D000328:Adult; D003324:Coronary Artery Disease / Q000235:genetics*; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008049:Lipase / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012723:Sex; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D015854:Up-Regulation
D017931:DNA Primers; D018076:DNA, Complementary; D007457:Iodine Radioisotopes; D013196:Dihydrotestosterone; D002785:Sterol O-Acyltransferase; D008049:Lipase