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.atherosclerosis ͉ androgens ͉ anastrazole ͉ mice ͉ estrogen

Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis

“…We subsequently demonstrated this possibility in LDLR Ϫ/Ϫ male mice and further demonstrated that this attenuating effect of testosterone on atherogenesis was abolished in the presence of an inhibitor of aromatase (8). The present work was undertaken to elucidate the cellular mechanism by which testosterone attenuates atherogenesis.…”

“…RNA extraction and purification were done by using RNeasy mini kit as described by the manufacturer's protocol (Qiagen, Chatsworth, CA). Total cellular RNA (3 g) was used for RT-PCR analysis of human aromatase with 50 units of Moloney murine leukemia virus reverse transcriptase at 42°C for 25 min, as described (8). The resulting cDNA samples were PCRamplified with the Gene Amp RNA PCR kit (Perkin-Elmer) according to the manufacturer's protocol.…”

“…Testosterone administration has been reported to increase the extent of atherosclerosis in subhuman primates (5) and in rabbits (6). On the other hand, its administration has also been reported to cause a decrease in atherosclerosis in castrated male rabbits (7) and in LDL-receptor knockout (LDLR Ϫ/Ϫ ) mice (8). Similarly, androgens seem to have an antiatherogenic effect in men (9), and testosterone has been reported to be an effective antianginal agent (10).…”

Hormonal effects on blood vessels

“…94 Regarding the role of AR, conflicting findings have been reported. Nathan et al 95 demonstrated the inhibitory effects of testosterone on fatty streak formation in castrated low-density lipoprotein receptor-deficient male mice, but the effects of testosterone were abrogated by treatment with an aromatase inhibitor, suggesting that estradiol converted from testosterone had a major role. Conversely, Qiu et al 91 showed that nonaromatizable dihydrotestosterone suppressed atherosclerosis formation in castrated male rabbits, indicating a role for AR.…”

Regulated expression of the prostacyclin receptor (IP) gene by androgens within the vasculature: Combined role for androgens and serum cholesterol

“…Conversely, testosterone is also a major biosource of estrogens, whereby testosterone can be aromatised to estradiol [71]. Therefore, it has been proposed that cardioprotection afforded by androgens could be mediated through aromatisation to estradiol and signalling through the ER [72]. Given that E2 is a regulator of the PTGIR and the hIP promoter (PrmIP) contains a highly conserved functional ERE [23], the more active metabolite DHT which cannot be converted to estradiol by aromatase was used throughout this study.…”