Expedited review
Androgens Up-Regulate Atherosclerosis-Related Genes in Macrophages From Males But Not Females: Molecular Insights Into Gender Differences in Atherosclerosis

https://doi.org/10.1016/j.jacc.2003.07.002Get rights and content
Under an Elsevier user license
open archive

Abstract

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

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

Cited by (0)

Drs. Ng, Quinn, Jessup, and Death are supported by the National Health and Medical Research Council, and Dr. Celermajer is supported by the Medical Foundation, University of Sydney.