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

Abstract

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 exvivo by Vernier calipers, mice were euthanized, and tissueswere 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 2and 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 mayserve as a target for therapeutic agents for AAA in males.