A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall.
OBJECTIVE
Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs.


METHODS
We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture.


RESULTS
Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 micromol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner (P <.001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling.


CONCLUSIONS
These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA.
Nagashima
Hirotaka
H
Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Japan. mnagashih@hij.twmu.ac.jp
Aoka
Yoshikazu
Y
Sakomura
Yasunari
Y
Sakuta
Akiko
A
Aomi
Shigeyuki
S
Ishizuka
Naoko
N
Hagiwara
Nobuhisa
N
Kawana
Masatoshi
M
Kasanuki
Hiroshi
H
D001012:Aorta, Abdominal / Q000166:cytology / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D007564:Japan; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage*; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C086276:cerivastatin; D020780:Matrix Metalloproteinase 9