Effect of Simvastatin on MMPs and TIMPs in Human Brain Endothelial Cells and Experimental Stroke
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Effect of Simvastatin on MMPs and TIMPs in Human Brain Endothelial Cells and Experimental Stroke Björn Reuter & Claus Rodemer & Saskia Grudzenski & Stephen Meairs & Peter Bugert & Michael G. Hennerici & Marc Fatar
Received: 4 September 2014 / Revised: 15 October 2014 / Accepted: 26 November 2014 # Springer Science+Business Media New York 2014
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. B. Reuter (*) : C. Rodemer : S. Grudzenski : S. Meairs : M. G. Hennerici : M. Fatar Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany e-mail: [email protected] P. Bugert Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, German Red Cross Blood Service Baden-Wuerttemberg–Hesse, Heidelberg University, Mannheim, Germany Present Address: B. Reuter Department of Neurology, University Hospital of Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany
Keywords MMPs . TIMPs . OGD . Endothelial cells . Stroke . Statins
Introduction Both ischemic and hemorrhagic strokes are associated with altered expression, secretion, and activation of matrix metalloproteinases (MMPs), thereby contributing to disruption of the blood–brain barrier (BBB) which subsequently results in vascular edema and blood extravasation [1]. Particularly, MMP-2 and MMP-9 are involved in this process. The tissue inhibitors of metalloproteinase (TIMPs) as endogenous MMP inhibitors might have a protective role for the BBB integrity in stroke [2]. Clinical studies and meta-analyses revealed that statins might support a favorable functional outcome after stroke [3, 4]. Since positive effects of statins on the MMP metabolism in the human vascular system were demonstrated in vitro and in vivo, we hypothesized that they might ameliorate the MMP metabolism during the course of acute stroke [5, 6]. To address this question, we investigated the profile o
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