Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.
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.


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.
Zhang
Yali
Y
Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
Naggar
Jack C
JC
Welzig
C Michael
CM
Beasley
Debbie
D
Moulton
Karen S
KS
Park
Ho-Jin
HJ
Galper
Jonas B
JB
D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D048748:MAP Kinase Kinase Kinase 3 / Q000037:antagonists & inhibitors*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001057:Apolipoproteins E; D001549:Benzamides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000804:Angiotensin II; D019821:Simvastatin; D048748:MAP Kinase Kinase Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9