Abstract 341: Cytochrome P450 1b1 Is Essential For The Development Of Aortic Aneurysm In Apoe Knockout Mice

Abstract

Previously we showed that the development of hypertension is dependent on cytochrome P450 (CYP)1B1 activity. This study addressed the role of CYP1B1 in the pathogenesis of angiotensin II (Ang II)-induced aortic aneurysms. Sixteen week old male ApoE-/-/Cyp1b1+/+ and ApoE-/-/Cyp1b1-/- mice were administered Ang II (700 ng/min/Kg) or its vehicle (veh) for one month using mini-osmotic pumps implanted subcutaneously. A separate group of ApoE-/-/Cyp1b1+/+ mice receiving Ang II were injected twice weekly with the selective inhibitor of CYP1B1 2,3',4,5'-tetramethoxystilbene (TMS) (300 μg/Kg) or its vehicle DMSO (i.p.). Ultrasound studies showed that Ang II infusion produced abdominal aortic aneurysms in the ApoE-/-/Cyp1b1+/+ mice that were prevented by simultaneous treatment with TMS or Cyp1b1 gene deletion. Ang II-induced aortic aneurysms were characterized by increased degradation of collagen, elastin and actin; and expression of matrix metalloproteinases MMP2, 9 as well as markers of inflammation including macrophages, and CD3+ T cells, and increased production of reactive oxygen species in the ApoE-/-/Cyp1b1+/+ mice; these changes were minimized by treatment with TMS or Cyp1b1 gene deletion (Table 1). Microarray analysis indicated downregulation (>1.5 fold) of markers of angiogenesis and inflammation including Angiopoeitin 2, P-selectin, platelet derived growth factor receptor, MMP 2, 9 and 12, and CD276 in the ApoE-/-/Cyp1b1-/- mice. These data suggest that Ang II-induced abdominal aortic aneurysms and associated pathophysiological changes in ApoE-/- mice are mediated by CYP1B1 via increased inflammation and oxidative stress.