Abstract 449: Develoment of Endothelin-1 Induced Aneurysms in High-Fat Diet-Fed Apolipoprotein E Knockout Mice Through a Mechanism Involving Oxidative Stress and Inflammatory Cell Infiltration
Background: Endothelin (ET)-1 has been implicated in the pathogenesis of atherosclerosis. Plasma and tissue ET-1 are increased in human and animal with atherosclerosis. ET-1 overexpression exacerbates high-fat diet (HFD)-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mouse. Abdominal aorta aneurysms (AAA) occur in association with atherosclerosis. We hypothesized that ET-1-induced ROS and inflammation would increase the occurrence of AAA in HFD fed apoE-/- mice.
Design and methods: Eight-week-old male transgenic mice overexpressing preproET-1 in the endothelium (eET-1), apoE-/-, eET-1/apoE-/- and wild type mice were fed a HFD for 8 weeks. Suprarenal aortic perimeter was determined using Oil Red O stained-sections. ROS production using dihydroethidium staining and monocyte/macrophage and T cell infiltration using immunofluorescence with MOMA-2 and anti-CD4 antibodies, respectively, were determined in perivascular fat and media in suprarenal aorta sections.
Results: Aneurysms were observed at a suprarenal level in 6 of 15 eET-1/apoE-/- compared to none of 15 apoE-/- (P<0.05). The aortic perimeter was increased 2.5-fold in eET-1/apoE-/- with AAA compared to apoE-/- (P<0.01). ROS production was increased 2.8- and 3.8-fold in perivascular fat and media of eET-1/apoE-/- compared to apoE-/-, respectively (P<0.05). Monocyte/macrophage infiltration was increased 2.6-fold in perivascular fat of eET-1/apoE-/- compared to apoE-/- (P<0.01). CD4+ T cell infiltration was observed in perivascular fat and plaque of 6 eET-1/apoE-/- compared to none of 6 apoE-/-, respectively (P<0.05).
Conclusions: These results suggest that ET-1 plays an important role in development of AAA by increasing oxidative stress and monocyte/macrophage and T cell infiltration in the aorta.
- © 2012 by American Heart Association, Inc.