Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis

J Am Coll Cardiol. 2003 Oct 1;42(7):1306-13. doi: 10.1016/j.jacc.2003.07.002.


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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Coronary Artery Disease / genetics*
  • DNA Primers
  • DNA, Complementary / genetics
  • Dihydrotestosterone / pharmacology*
  • Female
  • Humans
  • Iodine Radioisotopes
  • Lipase / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Male
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sex*
  • Sterol O-Acyltransferase / metabolism
  • Up-Regulation


  • DNA Primers
  • DNA, Complementary
  • Iodine Radioisotopes
  • Dihydrotestosterone
  • Sterol O-Acyltransferase
  • Lipase