Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats.
OBJECTIVE
The pathophysiology of cerebral aneurysms (CAs) is linked to chronic inflammation and degradation of extracellular matrix in vascular walls. Because statins have protective effects on various vascular diseases independent of their lipid-lowering effects, we investigated the effect of simvastatin on CA progression.


METHODS
CAs were induced in Sprague-Dawley rats with or without oral administration of simvastatin. The size and media thickness of CAs was evaluated 3 months after aneurysm induction. Expression of macrophage chemoattractant protein-1, vascular cell adhesion molecule-1, endothelial nitric oxide synthase, interleukin-1beta, inducible nitric oxide synthase, matrix metalloproteinase-2, and matrix metalloproteinase-9 in aneurysmal walls was examined by reverse transcriptase-polymerase chain reaction and immunohistochemistry. To examine whether simvastatin has a suppressive effect on preexisting CAs, simvastatin administration started at 1 month after aneurysm induction.


RESULTS
Rats treated with simvastatin exhibited a significant increase in media thickness and a significant reduction in aneurysmal size compared with control rats. Treatment with simvastatin resulted in reduced expression of macrophage chemoattractant protein-1 and vascular cell adhesion molecule-1, increased expression of endothelial nitric oxide synthase, and reduced the number of macrophage infiltration. In quantitative polymerase chain reaction and immunohistochemistry, simvastatin significantly inhibited upregulated expression of interleukin-1beta, inducible nitric oxide synthase, matrix metalloproteinase-2, and matrix metalloproteinase-9 associated with CA progression. Gelatin zymography revealed decreased activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 in aneurysmal walls by simvastatin treatment. Simvastatin also effectively inhibited aneurysm enlargement and thinning of the media of preexisting CAs.


CONCLUSIONS
Treatment with simvastatin suppresses the development of CAs by inhibiting inflammatory reactions in aneurysmal walls. Simvastatin also has a preventive effect on the progression of preexisting CAs. Simvastatin is a promising candidate of a novel medical treatment for the prevention of CA progression.
Aoki
Tomohiro
T
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kataoka
Hiroharu
H
Ishibashi
Ryota
R
Nozaki
Kazuhiko
K
Hashimoto
Nobuo
N
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D019010:Vascular Cell Adhesion Molecule-1; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9