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Arterioscler Thromb Vasc Biol ; 29(11): 1764-71, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19729613

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.


Subject(s)
Aortic Aneurysm, Abdominal/prevention & control , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , MAP Kinase Kinase Kinase 3/antagonists & inhibitors , Simvastatin/pharmacology , 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
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