Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase

Abstract

The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription-PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.

Figure 1

Atherosclerotic lesions at the aortic root of male C57BL/6J, LDLR^−/− mice. The mice were divided into the following groups: (i) TI (n = 11); (ii) TI + A (n = 11); (iii) Orch + P (n = 11); (iv) Orch + T (n = 8); (v) Orch + T + A (n = 10); and (vi) Orch + 17β-E₂ (n = 6). Animals were fed a Western diet for 8 weeks. Values are expressed as mean ± SEM. *, P < 0.05 vs. TI, **, P < 0.05 vs. Orch + P, and ***, P < 0.05 vs. Orch + T

Figure 2

RT-PCR analysis of aromatase mRNA from mouse brain (lane 1), mouse brain (lane 2), and LDLR^−/− mouse aorta (lane 3).

Figure 3

Immunohistochemical analysis of aromatase expression in the vessel wall of LDLR^−/− mice. Frozen sections were fixed with acetone, and incubated with a rabbit polyclonal antibody against mouse aromatase. (A) Section on which incubation with polyclonal antibody was omitted. (B) Section incubated with polyclonal antibody. Original magnification was ×40.