title: The rapid lipopolysaccharide-induced release of matrix metalloproteinases 9 is suppressed by simvastatin.
abstract: A rapid increase in matrix metalloproteinase-9 (MMP-9) expression by stimulated leukocytes is common in many diseases. Recent evidence suggests that the beneficial effects of statins are mediated in part by the suppression of MMP-9 release. In this study, we investigated the effect of statin on MMP-9 expression and its antagonist, tissue inhibitor of metalloproteinase-1 (TIMP-1) in LPS-stimulated leukocytes. Rat neutrophils and monocytes were stimulated with lipopolysaccharide (LPS) in the presence of simvastatin. MMP-9 secretion and mRNA expression were analyzed using ELISA and RT-PCR, respectively. Total MMP-9 protein production was measured by Western blot analysis. Potential signal transduction pathways responsible for MMP-9 production were investigated using luciferase reporter assays (NF-κB), pull-down assays (RhoA), and pharmacological inhibition. Our data show that MMP-9 and TIMP-1 expression are differentially induced by LPS in neutrophils and monocytes. We showed that rapid MMP-9 release occurred mainly via secretion from intracellular stores. Moreover, we showed that statin significantly suppressed LPS-induced MMP-9 release and mRNA expression in a time- and concentration-dependent manner. We also evaluated that simvastain postponed the rapid LPS-induced MMP-9 release for about 20 min. In conclusion, we demonstrated that the suppressive effect of simvastatin on LPS-stimulated MMP-9 release does not occur via the NF-κB pathway and the MAPKs pathway, but via the RhoA/ROCK pathway.
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Dan-Dong
authors.initials: DD
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Pang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Jin-Ning
authors.initials: JN
authors.lastname: Song
authors.affiliation: Department of Imaging Center, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Yong-Lin
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Bin-Fei
authors.initials: BF
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Ma
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D008070:Lipopolysaccharides / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000276:immunology; D020742:rhoA GTP-Binding Protein / Q000276:immunology
chemical_list: D000924:Anticholesteremic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019821:Simvastatin; D054460:rho-Associated Kinases; D020780:Matrix Metalloproteinase 9; D020742:rhoA GTP-Binding Protein
keywords: MMP-9; RhoA/ROCK; TIMP-1; leukocyte; lipopolysaccharide; simvastatin