1. Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.
- Author
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Zhang Y, Naggar JC, Welzig CM, Beasley D, Moulton KS, Park HJ, and Galper JB
- Subjects
- Angiotensin II, Animals, Aortic Aneurysm, Abdominal chemically induced, Aortic Aneurysm, Abdominal metabolism, Aortic Aneurysm, Abdominal pathology, Apolipoproteins E metabolism, Apolipoproteins E pharmacology, Benzamides pharmacology, Blood Pressure drug effects, Blotting, Western, Disease Models, Animal, Immunohistochemistry, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Random Allocation, Reference Values, Renin-Angiotensin System drug effects, Aortic Aneurysm, Abdominal prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, MAP Kinase Kinase Kinase 3 antagonists & inhibitors, Simvastatin pharmacology
- Abstract
Objective: Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE(-/-)) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation., Methods and Results: ApoE(-/-) mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells., Conclusions: These data support the conclusion that simvastatin interferes with AAA formation induced by AngII in ApoE(-/-) mice at least in part via ERK inhibition.
- Published
- 2009
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