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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1764.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Simvastatin Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-Knockout Mice

Possible Role of ERK

Yali Zhang; Jack C. Naggar; C. Michael Welzig; Debbie Beasley; Karen S. Moulton; Ho-Jin Park; Jonas B. Galper

From the Molecular Cardiology Research Institute, Department of Medicine (Y.Z., J.C.N., D.B., H.-J.P., J.B.G.), Tufts Medical Center, Tufts University School of Medicine, Boston, Mass; the Department of Neurosciences (C.M.W.), Medical University of South Carolina, Charleston; the Cardiology Division (K.S.M.), University of Colorado Denver, Aurora.

Correspondence to Jonas B. Galper, Molecular Cardiology Research Institute, Box #8486, Tufts Medical Center, 750 Washington St, Boston, MA 02111. E-mail Jgalper{at}tuftsmedicalcenter.org

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.

Infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE^–/–) mice is an animal model for abdominal aortic aneurysm (AAA). Our data support the conclusion that simvastatin interferes with AngII-stimulated AAA formation in these mice at least in part via the inhibition of ERK.

Key Words: angiotensin II • abdominal aortic aneurysm • statin • ERK inhibition • angiogenesis