title: Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue.
abstract: HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) have been suggested to attenuate abdominal aortic aneurysm (AAA) growth. However, the effects of statins in human AAA tissues are not fully elucidated. The aim of this study was to investigate the direct effects of statins on proinflammatory molecules in human AAA walls in ex vivo culture. Simvastatin strongly inhibited the activation of nuclear factor (NF)-κB induced by tumor necrosis factor (TNF)-α in human AAA walls, but showed little effect on c-jun N-terminal kinase (JNK) activation. Simvastatin, as well as pitavastatin significantly reduced the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and epithelial neutrophil-activating peptide (CXCL5) under both basal and TNF-α-stimulated conditions. Similar to statins, the Rac1 inhibitor NSC23766 significantly inhibited the activation of NF-κB, accompanied by a decreased secretion of MMP-9, MCP-2 and CXCL5. Moreover, the effect of simvastatin and the JNK inhibitor SP600125 was additive in inhibiting the secretion of MMP-9, MCP-2 and CXCL5. These findings indicate that statins preferentially inhibit the Rac1/NF-κB pathway to suppress MMP-9 and chemokine secretion in human AAA, suggesting a mechanism for the potential effect of statins in attenuating AAA progression.
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. yoshimko@yamaguchi-u.ac.jp.|Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi 753-8502, Japan. yoshimko@yamaguchi-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. nagasawa.ayako@gmail.com.|Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Science, Niigata 951-8510, Japan. nagasawa.ayako@gmail.com.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nagasawa
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. junkud@yb3.so-net.ne.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kudo
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. m-onoda0911@cap.ocn.ne.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Onoda
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. morikage@yamaguchi-u.ac.jp.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Morikage
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. akirafut@a011.broada.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Furutani
authors.affiliation: Cardiovascular Research Institute, Kurume University, Kurume 830-0011, Japan. haoki@med.kurume-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan. kimikazu@yamaguchi-u.ac.jp.
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology*; D054412:Chemokine CCL8 / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000873:Anthracenes; C515453:CCL8 protein, human; D054412:Chemokine CCL8; D054365:Chemokine CXCL5; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; C487513:NSC 23766; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D019821:Simvastatin; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein
keywords: abdominal aortic aneurysm; nuclear factor-κB; statin