Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe^-/- Male Mice

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1-generated metabolite of testosterone, 6β-hydroxytestosterone (6β-OHT), contributes to Ang II-induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β-OHT to Ang II-induced AAA development in Apoe^-/- male mice. Methods and Results Intact or castrated Apoe^-/-/Cyp1b1^+/+ and Apoe^-/-/Cyp1b1^-/- male mice were infused with Ang II or its vehicle for 28 days, and administered 6β-OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II-infused Apoe^-/-/Cyp1b1^+/+ mice, compared with vehicle-treated mice, which were minimized in castrated Apoe^-/-/Cyp1b1^+/+ and intact Apoe^-/-/Cyp1b1^-/- mice infused with Ang II. Treatment with 6β-OHT significantly restored the incidence and severity of AAAs in Ang II-infused castrated Apoe^-/-/Cyp1b1^+/+ and intact Apoe^-/-/Cyp1b1^-/- mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II-infused intact Apoe^-/-/Cyp1b1^-/- mice. Conclusions Our results indicate that the testosterone-cytochrome P450 1B1-generated metabolite 6β-OHT contributes to Ang II-induced AAA development in Apoe^-/- male mice.