Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice.
OBJECTIVE
To determine if treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) can influence the development of experimental abdominal aortic aneurysms (AAAs).


BACKGROUND
AAAs are associated with atherosclerosis, chronic inflammation, and matrix metalloproteinase (MMP)-mediated connective tissue destruction. Because statins exert antiinflammatory activities independent of their lipid-lowering effects, these agents may help suppress aneurysmal degeneration.


METHODS
C57Bl/6 wild-type and hypercholesterolemic apoE-deficient mice underwent transient perfusion of the aorta with elastase followed by subcutaneous treatment with either 2 mg/kg simvastatin per day or vehicle. Aortic diameter (AD) was measured before and 14 days after elastase perfusion. The extent of aortic dilatation (DeltaAD) was determined with AAAs defined as DeltaAD >100%.


RESULTS
Wild-type mice treated with simvastatin exhibited a 21% reduction in DeltaAD and a 33% reduction in AAAs compared with vehicle-treated controls. Suppression of AAAs in simvastatin-treated mice was associated with preservation of medial elastin and vascular smooth muscle cells, as well as a relative reduction in aortic wall expression of MMP-9 and a relative increase in expression of TIMP-1. In hypercholesterolemic apoE-deficient mice, treatment with simvastatin was associated with a 26% reduction in DeltaAD and a 30% reduction in AAAs. Treatment with simvastatin had no effect on serum cholesterol levels in either normal or hypercholesterolemic mice.


CONCLUSIONS
Treatment with simvastatin suppresses the development of experimental AAAs in both normal and hypercholesterolemic mice. The mechanisms of this effect are independent of lipid-lowering and include preservation of medial elastin and smooth muscle cells, as well as altered aortic wall expression of MMPs and their inhibitors.
Steinmetz
Eric F
EF
Department of Surgery (Section of Vascular Surgery), Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Buckley
Celine
C
Shames
Murray L
ML
Ennis
Terri L
TL
Vanvickle-Chavez
Sarah J
SJ
Mao
Dongli
D
Goeddel
Lee A
LA
Hawkins
Cherady J
CJ
Thompson
Robert W
RW
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D004549:Elastin / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis; D017540:Tunica Media / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; D019821:Simvastatin; D020782:Matrix Metalloproteinases