Abstract P325: 6β-hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Hyperlipidemic Male Mice

Abstract

It is well established that men have a higher risk of developing cardiovascular diseases including hypertension and abdominal aortic aneurysms (AAAs) than do premenopausal women of the same age. Angiotensin II (Ang II) induces abdominal aortic aneurysms (AAA) to a greater degree in male than in female mice, and castration protects male mice against Ang II-induced AAAs. Previously we reported that cytochrome P450 (CYP) 1B1 contributes to Ang II-induced hypertension as well as AAAs in male mice. Recently we have shown that CYP1B1-testosterone derived metabolite 6β-hydroxytestosterone (6β-OHT), mediates Ang II-induced hypertension and cardiac and renal fibrosis in male mice. The current study was conducted to determine the contribution of CYP 1B1-generated 6β-OHT to Ang II-induced AAAs in male mice. Sixteen-week old intact or castrated male, ApoE -/- / Cyp1b1 +/+ (ApoE KO) and ApoE -/- / Cyp1b1 -/- (DKO) mice were infused with 700 ng/kg/min Ang II or its vehicle (s.c.) with osmotic minipumps for 28 days. These mice were also injected with 6β-OHT (15 μg/g body weight, i.p. every 3rd day) or its vehicle for the duration of the experiment. The abdominal aortas were analyzed for development of AAAs (a 50% increase in external abdominal aortic diameter). Ang II significantly increased ( P <0.05) the incidence as well as severity of AAAs in intact ApoE KO mice (66.7% incidence; 8 of 12), compared to 0% (0 of 5) incidence in vehicle-treated mice, which were minimized in castrated ApoE KO (0% incidence; 0 of 9) and intact DKO (0% incidence; 0 of 9) mice. Administration of 6β-OHT restored the incidence and severity of AAAs in Ang II-infused castrated ApoE KO (44.4% incidence; 4 of 9) and intact DKO (62.5% incidence; 10 of 16) mice. In contrast, treatment with testosterone failed to increase the incidence and severity of Ang II-induced AAAs in the intact DKO mice (10% incidence; 1 of 10). Histological analysis of sections of the abdominal aortas confirmed the above results, along with disruption of elastin fibers, a pathological hallmark of AAAs. These data suggest that CYP1B1-generated testosterone metabolite, 6β-OHT, contributes to Ang II-induced AAAs in hyperlipidemic male mice. Therefore, inhibitors of CYP1B1 could be useful in the treatment of AAAs in males with hyperlipidemia.