title: Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke.
abstract: Clinical studies demonstrated favorable effects of statins in stroke beyond lipid-lowering effects. In acute stroke, the disruption of the blood-brain barrier (BBB) is mediated by matrix metalloproteinases (MMPs). A modified MMP metabolism may account for the beneficial effects of statins. Cultured human brain microvascular endothelial cells (BMECs) were pretreated with simvastatin and subjected to oxygen glucose deprivation (OGD). Gene expression and protein secretion of MMP-2 and MMP-9 and the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were measured by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Simvastatin significantly dampened the expression but not secretion of MMP-2 under OGD. MMP-9 synthesis rate was low and unaffected by simvastatin treatment, while the gene expression and protein secretion of TIMP-1 and TIMP-2 were both strongly induced. Our results provide evidence for a positive effect of simvastatin on the MMP metabolism in human BMECs and experimental stroke mainly by means of the increased expression and secretion of TIMP-1 and TIMP-2.
authors.affiliation: Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany, bjoern.reuter@uniklinik-freiburg.de.
authors.forename: Björn
authors.initials: B
authors.lastname: Reuter
authors.forename: Claus
authors.initials: C
authors.lastname: Rodemer
authors.forename: Saskia
authors.initials: S
authors.lastname: Grudzenski
authors.forename: Stephen
authors.initials: S
authors.lastname: Meairs
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hennerici
authors.forename: Marc
authors.initials: M
authors.lastname: Fatar
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019821:Simvastatin; D020782:Matrix Metalloproteinases; D005947:Glucose