Abstract 1036: Simvastatin inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E Knockout Mice
Chronic infusion of Angiotensin II (AngII) was shown to induce abdominal aortic aneurysms (AAA) in Apolipoprotein E Knockout (ApoE-KO) mice. However, the effect of HMG-CoA reductase inhibitors (statins) on AngII-induced AAA has not been studied. Male ApoE-KO mice (6 – 8 months old) were treated for 4 weeks with either saline or AngII via osmotic minipumps. The AngII group was subdivided into 2 groups (n=8 each) injected either with saline (placebo) or simvastatin (simva) (10 mg/kg/day). Simva had no effect on blood pressure and lipid levels. The mean diameter of the abdominal suprarenal aorta increased from 1.02±0.04 mm in controls to 2.04±0.26 mm (p<0.01) in the placebo-treated AngII group with rupture and thrombus formation. Aorta diameters decreased to 1.23±0.31mm (p<0.05) in the simva group and were free of thrombus. The elastin layer was ruptured in the placebo group and intact in the simva group. Mac3+-stained macrophage area in AAA decreased 69.1±4.1% in the simva group compared to the placebo group (p<0.01). Ang II treated mice demonstrated extensive vasa vasorum in the region of AAA as measured by CD31 staining of whole aortic mounts, which was completely inhibited by simva. Neovascularization measured by CD31 staining of aneurysmal tissues from the AngII group was decreased 51.1± 3.6% (n=14, p<0.05) by simva. In order to determine whether simva interferes with AngII-induced neovascularization, the effect of simva on AngII-induced tube formation of human vascular endothelial cells (HUVECs) grown on Matrigel was determined. AngII increased tube formation 54± 8% (n=6, p<0.05). This effect was completely inhibited by simva in a dose dependent manner (0.1–1 μM). Western blot analysis of extracts from AAA in placebo treated AngII mice demonstrated 2.3± 0.3% fold increase in p-ERK compared to controls. This effect was reversed completely by simva. These data demonstrated that simva attenuates AngII-induced AAA formation independent of effects on blood pressure and lipid lowering and suggest that inhibition of neovascularization might play a role in this process. Given the role of ERK in angiogenesis and inflammation, ERK-targeted therapy, which is currently in clinical trials for tumor chemotherapy, might provide a nonsurgical treatment for AAA.