Simvastatin suppresses experimental aortic aneurysm expansion.
OBJECTIVE
Abdominal aortic aneurysm (AAA) formation is a result of inflammation and extracellular matrix (ECM) remodeling mediated by matrix metalloproteinases (MMPs). Hydroxymethylglutaryl-coenzyme A inhibitors (statins), although clinically used as lipid-lowering agents, have also been demonstrated to have anti-inflammatory effects. This study was designed to determine whether the hydroxymethylglutaryl-coenzyme A inhibitor simvastatin suppresses aneurysm formation in an elastase-induced rat AAA model.


METHODS
Aneurysms were created in adult male Wistar rats by infusion of elastase into isolated infrarenal aortic segments. The rats were randomized to receive either simvastatin (n = 17) or placebo (n = 17) by gastric lavage daily starting the day before surgery. The rats were euthanized and the infrarenal aortas harvested on postoperative day 7. Aortic diameters were measured before infusion, immediately after infusion, and at the time of harvesting. Protein expression was measured by immunoblot analysis. Gene expression profiling using Affymetrix U34A rat genome chips was performed to identify changes in gene expression caused by simvastatin treatment.


RESULTS
Mean aneurysm diameter was significantly less in the simvastatin treatment group compared with controls (3.4 +/- 0.08 mm vs 4.3 +/- 0.19 mm; P = .0001). MMP-9 and nuclear factor-kappaB protein levels were decreased in the aortas of simvastatin-treated animals. Gene microarray analysis revealed 315 genes with statistically significant changes in expression (P < .05) in the simvastatin group. Genes related to inflammation, ECM remodeling, and oxidative stress function were downregulated. These included genes for interleukin 1, interleukin 4, inducible nitric oxide synthase, P-selectin, platelet-derived growth factor alpha, tumor necrosis factor, and several chemokines.


CONCLUSIONS
Simvastatin significantly suppresses experimental aneurysm expansion and reduces protein levels of MMP-9 and nuclear factor-kappaB. Gene array analysis provides evidence that several mediators of inflammation, matrix remodeling, and oxidative stress are downregulated by simvastatin treatment. This suggests that simvastatin inhibits AAA formation by blocking the expression of certain proinflammatory genes. Simvastatin may be useful as an adjuvant therapy to suppress the growth of small aneurysms.
Kalyanasundaram
Arun
A
Section of Vascular Surgery, Weis Center for Research, Geisinger Clinic, Danville, PA 17822-2150, USA.
Elmore
James R
JR
Manazer
James R
JR
Golden
Alicia
A
Franklin
David P
DP
Galt
Spencer W
SW
Zakhary
Emad M A
EM
Carey
David J
DJ
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin