Changes In Expression Of MMP-9 Research Articles

The Effect of Bay Leaf Extract (Syzygium polyanthum) on Reducing Overexpression of Matrix Metalloproteinases-13 in Acute Coronary Syndrome

AIM: The objective of the study was to determine the inhibitory effect of bay leaf (Syzygium polyanthum) on matrix metalloproteinases (MMPs) (MMP-9 and MMP-13) inhibitory effect in surgery-induced acute coronary syndrome (ACS) rat model.
 METHODS: This study was experimental animal study. Thirty-two surgery-induced ACS Wistar rats (Rattus norvegicus) divided into 16 bay leaf extract (treatment) group and 16 control groups were sacrificed on days 1, 3, 7, and 14 after induction. Expressions of MMP-9 and MMP-13 were determined by immunohistochemistry and its scoring was assessed by two-blinded experienced pathologists. The immunohistochemical scoring of MMP-9 and MMP-13 between groups was analyzed using independent sample t-test and within groups by using one-way ANOVA test.
 RESULTS: The expression of MMP-13 in treatment group was decreased compared to control group on days 7 and 14 (p = 0.001 and p = 0.015, respectively). Compared to day 1, the reduction expression of MMP-13 was significant in both control group and treatment group (p = 0.009 and p = 0.003, respectively). There were no significant changes in expression of MMP-9 between groups, and within control group and treatment group.
 CONCLUSION: Bay leaf can reduce the overexpression of MMP-13 in surgery-induced ACS rat model. Bay leaf extract can be considered to be given as an adjuvant to prevent cardiovascular adverse event and adverse cardiac remodeling post-ACS.

Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells.

Cobalt-containing metal-on-metal hip replacements are associated with adverse reactions to metal debris (ARMD), including inflammatory pseudotumours, osteolysis, and aseptic implant loosening. The exact cellular and molecular mechanisms leading to these responses are unknown. Cobaltions (Co2+) activate human Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to Gram negative bacterial lipopolysaccharide (LPS).We investigated the effect of Co2+-mediated TLR4 activation on human microvascular endothelial cells (HMEC-1), focusing on the secretion of key inflammatory cytokines and expression of adhesion molecules. We also studied the role of TLR4 in Co2+-mediated adhesion molecule expression in MonoMac 6 macrophages.We show that Co2+ increases secretion of inflammatory cytokines, including IL-6 and IL-8, in HMEC-1. The effects are TLR4-dependent as they can be prevented with a small molecule TLR4 antagonist. Increased TLR4-dependent expression of intercellular adhesion molecule 1 (ICAM1) was also observed in endothelial cells and macrophages. Furthermore, we demonstrate for the first time that Co2+ activation of TLR4 upregulates secretion of a soluble adhesion molecule, sICAM-1, in both endothelial cells and macrophages. Although sICAM-1 can be generated through activity of matrix metalloproteinase-9 (MMP-9), we did not find any changes in MMP9 expression following Co2+ stimulation.In summary we show that Co2+ can induce endothelial inflammation via activation of TLR4. We also identify a role for TLR4 in Co2+-mediated changes in adhesion molecule expression. Finally, sICAM-1 is a novel target for further investigation in ARMD studies.

Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves: A Histopathologic, Immunohistochemical, and Ultrastructural Study.

The hallmarks of calcific aortic valve disease (CAVD) are the significant quantitative and qualitative changes that occur in the extracellular matrix (ECM), which ultimately lead to increased leaflet stiffness and obstruction of left ventricular outflow. Mounting evidence suggests that ECM remodeling not only contribute to valve cell dysfunction but also alter certain cell signaling pathways responsible for the initiation and progression of the disease state. Matrix metalloproteinases (MMPs), collectively called matrixins, are a family of enzymes known to participate in numerous ECM remodeling events during embryonic development and in disease. The aim of the present study was to evaluate whether changes in MMP-9 expression might be involved in the pathophysiology of CAVD. For this purpose, we have analyzed a total of 19 pathologic valves from patients who underwent aortic valve replacement for calcific aortic stenosis. Microscopically, the cusp tissue showed diffuse fibrosis, neovascularization, and abnormal ECM remodeling with collagen disorganization and mineralization. Western blot and immunohistochemical analyses have been performed on both the areas overlying and remote from the mineral deposits. Protein expression data evidenced a significant upregulation of MMP-9 in the calcified lesion area. Consistent with these observations, immunohistochemistry demonstrated that MMP-9 protein was almost exclusively localized near or around the mineralized nodules, whereas was generally quite weak or absent in areas devoid of any calcification. Our data suggest that MMP-9 may play a key role in CAVD probably by promoting the fibrotic and procalcific remodeling of the ECM.

Thrombin-induced Migration and Matrix Metalloproteinase-9 Expression Are Regulated by MAPK and PI3K Pathways in C6 Glioma Cells

Glioblastoma multiforme is one of the most common and aggressive tumors in central nervous system. It often possesses characteristic necrotic lesions with hemorrhages, which increase the chances of exposure to thrombin. Thrombin has been known as a regulator of MMP-9 expression and cancer cell migration. However, the effects of thrombin on glioma cells have not been clearly understood. In the present study, influences of thrombin on glioma cell migration were examined using Boyden chamber migration assay and thrombin-induced changes in MMP-9 expression were measured using zymography, semi-quantitative RT-PCR, and Western blotting. Furthermore, underlying signaling pathways by which thrombin induces MMP-9 expression were examined. Thrombin-induced migration and MMP-9 expression were significantly potentiated in the presence of wortmannin, a PI3K inhibitor, whereas MAPK inhibitors suppressed thrombin-induced migration and MMP-9 expression in C6 glioma cells. The present data strongly demonstrate that MAPK and PI3K pathways evidently regulate thrombin-induced migration and MMP-9 expression of C6 glioma cells. Therefore, the control of these pathways might be a beneficial therapeutic strategy for treatment of invasive glioblastoma multiforme.

Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2

SUMMARYThe matrix metalloproteinase (MMP) family of extracellular proteases performs crucial roles in development and repair of the skeleton owing to their ability to remodel the extracellular matrix (ECM) and release bioactive molecules. Most MMP-null skeletal phenotypes that have been previously described are mild, thus permitting the assessment of their functions during bone repair in the adult. In humans and mice, MMP2 deficiency causes a musculoskeletal phenotype. In this study, we assessed the role of MMP2 during mouse fracture repair and compared it with the roles of MMP9 and MMP13. Mmp2 was expressed at low levels in the normal skeleton and was broadly expressed in the fracture callus. Treatment of wild-type mice with a general MMP inhibitor, GM6001, caused delayed cartilage remodeling and bone formation during fracture repair, which resembles the defect observed in Mmp9–/– mice. Unlike Mmp9- and Mmp13-null mutations, which affect both cartilage and bone in the callus, the Mmp2-null mutation delayed bone remodeling but not cartilage remodeling. This remodeling defect occurred without changes in either osteoclast recruitment or vascular invasion of the fracture callus compared with wild type. However, we did not detect changes in expression of Mmp9, Mmp13 or Mt1-Mmp (Mmp14) in the calluses of Mmp2-null mice compared with wild type by in situ hybridization, but we observed decreased expression of Timp2 in the calluses of Mmp2-, Mmp9- and Mmp13-null mice. In keeping with the skeletal phenotype of Mmp2-null mice, MMP2 plays a role in the remodeling of new bone within the fracture callus and impacts later stages of bone repair compared with MMP9 and MMP13. Taken together, our results indicate that MMPs play unique and distinct roles in regulating skeletal tissue deposition and remodeling during fracture repair.

Relationship between methamphetamine exposure and matrix metalloproteinase 9 expression

Matrix metalloproteinase (MMP) 9 is up regulated following various types of insults to the brain. Recent studies have also implicated MMP9 in neural remodeling after stimulant doses of methamphetamine (METH). The involvement of MMP9 in METH‐induced neurotoxicity, however, remains unclear and was thus evaluated in the present study. Male, Swiss Webster mice were injected with stimulant or toxic doses of METH. MMP9 gene expression was up regulated in the brain within 5 min. By 24 h, MMP9 gene expression returned to control levels in the stimulant treated mice, but remained elevated in animals exposed to toxic doses of METH. The development of neurotoxicity was evidenced between 1­7 days following METH exposure as depletions in striatal dopamine levels. However, this marker of METH neurotoxicity was not accompanied by concomitant changes in striatal MMP9 gene expression. In MMP9 knock out mice, neurotoxic dosing with METH produced depletions in striatal dopamine levels that were comparable to wild type mice. Although the absence of MMP9 did not affect METH neurotoxicity, the knock out mice exhibited the expected decrease in behavioral sensitization following repeated administration of stimulant doses of METH. Together, the data suggest that changes in MMP9 expression do not affect METH‐induced neurotoxicity, and may instead be contributing to remodeling of the nervous system.

Thrombin-dependent regulation of matrix metalloproteinase (MMP)-9 levels in human fetal membranes

Objective. Amniochorion matrix metalloproteinase (MMP)-9 levels increase during labor, reaching a maximum in patients with preterm premature rupture of membranes (PPROM). Bleeding is a major risk factor for PPROM. Since such hemorrhage into the tissue factor-enriched decidua induces intense thrombin formation, we determined whether thrombin stimulates MMP levels in amniochorionic membranes.Study design. Fetal membrane (amniochorion) cultures were maintained in media with and without thrombin, lipopolysaccharide (LPS), thrombin receptor agonist peptide (TRAP)-14, and the anti-inflammatory steroid, dexamethasone (DEX). Concentrations of MMP-9, MMP-1, and tissue inhibitor of metalloproteinase (TIMP)-1 in culture media were measured by ELISA and normalized to total cell protein.Results. The presence of thrombin induced MMP-9 levels. TRAP-14, a thrombin receptor agonist, also significantly increased MMP-9 levels, suggesting that thrombin-induced changes in MMP-9 expression were mediated through the thrombin receptor. Conversely, levels of MMP-1 and TIMP-1 were not affected by thrombin treatment, indicative of specificity of its action. The presence of LPS increased the concentration of MMP-9 and MMP-1. In contrast, DEX treatment significantly reduced MMP-9 levels.Conclusion. Our findings clearly demonstrated that thrombin treatment selectively increased the concentration of MMP-9 in culture media of amniochorionic membranes. Our results provide a potential mechanism through which alterations in hemostasis promote PPROM through thrombin-dependent stimulation of MMP-9.