Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

摘要

Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) II–induced abdominal aortic aneurysm (AAA). Male Apoe^−/−/Cyp1b1^+/+ and Apoe^−/−/Cyp1b1^−/− mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe^−/−/Cyp1b1^+/+ mice was coadministered the CYP1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe^−/−/Cyp1b1^+/+ mice; mice treated with TMS or Apoe^−/−/Cyp1b1^−/− mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased platelet-derived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe^−/−/Cyp1b1^−/− mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe^−/−/Cyp1b1^+/+ mice treated with TMS and in Apoe^−/−/Cyp1b1^−/− mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang II–induced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males.