Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development

Area of Science:

• Endocrinology
• Cardiovascular Biology
• Molecular Medicine

Background:

• The role of testosterone in atherosclerosis is complex due to its aromatization to estrogen.
• 5alpha-dihydrotestosterone (DHT), a non-aromatizable androgen, offers a model to study androgen-specific effects.
• Lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) is implicated in atherogenesis.

Purpose of the Study:

• To investigate the impact of DHT on rabbit atherogenesis.
• To examine the relationship between DHT, LOX-1, and foam cell formation.
• To elucidate the role of the androgen receptor (AR) in DHT's effects on atherosclerosis.

Main Methods:

• New Zealand white rabbits were divided into four groups: control, high-cholesterol diet (HCD), HCD with castration and placebo, and HCD with castration and DHT pellet.
• Atherosclerotic plaque area and foam cell formation in the aorta were assessed.
• LOX-1 mRNA expression in aortic intima was analyzed.
• In vitro studies used cultured macrophages from wild-type and AR-null mice treated with DHT and oxidized LDL.

Main Results:

• DHT treatment significantly attenuated HCD-induced aortic plaque area.
• DHT reduced foam cell formation in the aorta, primarily composed of macrophages.
• DHT suppressed LOX-1 mRNA expression in aortic foam cells.
• In cultured macrophages, DHT inhibited foam cell formation and suppressed LOX-1 and inflammatory cytokine expression.
• These effects were dependent on the presence of the androgen receptor (AR).

Conclusions:

• Physiological levels of DHT attenuate atherosclerosis development in rabbits.
• DHT's protective effect involves the suppression of intimal macrophage foam cell formation.
• The mechanism is partly mediated by the downregulation of LOX-1 expression via the androgen receptor.