Abstract 301: Cytochrome P450 1b1 is Essential for the Development of Aortic Aneurysm in ApoE Knockout Mice

Abstract

Previously we have shown that the development of hypertension and neointimal growth is dependent on cytochrome P450 (CYP)1B1 activity. This study was conducted to address the role of CYP1B1 in the development of angiotensin II (Ang II)-induced aortic aneurysms and associated pathogenesis. Sixteen week old male ApoE -/- /Cyp1b1 +/+ and ApoE -/- /Cyp1b1 -/- mice were administered Ang II (750 ng/min/Kg) or its vehicle for one month using micro-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 of these mice with TMS, and in ApoE -/- /Cyp1b1 -/- mice. Histological and immunohistochemical analysis of aortic aneurysms revealed that Ang II increased degradation of collagen, elastin and actin, increased expression of matrix metalloproteinases MMP2 and MMP9 as well as markers of inflammation including macrophages and CD3 + T cells and increased production of reactive oxygen species (ROS) in the ApoE -/- /Cyp1b1 +/+ mice; these changes were minimized by treatment of these mice with TMS and in ApoE -/- /Cyp1b1 -/- mice. These data suggest that Ang II induced abdominal aortic aneurysms and associated pathophysiological changes in ApoE -/- mice are mediated by CYP1B1 most likely via generation of ROS. Therefore, CYP1B1 could serve as a novel target for the development of agents to treat abdominal aortic aneurysms and associated pathogenesis.