Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes

Choi, Min Sik; Kim, Young Eun; Lee, Woo Jong; Choi, Ji Woong; Park, Gyu Hwan; Kim, Sun Don; Jeon, Se Jin; Go, Hyo Sang; Shin, Sun Mi; Kim, Won Ki; Shin, Chan Young; Ko, Kwang Ho

doi:10.1016/j.brainresbull.2008.02.031

Cited by 40 publications

(42 citation statements)

References 51 publications

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“…Because activation of PAR-1 promotes proinflammatory, proangiogenic, and transforming pathways, 29,30 it might be suggested that MMP-10 could be a mediator of thrombin-induced proinflammatory responses. Finally, under our experimental conditions thrombin was also able to induce MMP-9 mRNA and protein levels (supplemental Figure II), in agreement with previous data reported in other cell types, 31 emphasizing the potential role of thrombin in vascular remodeling by modulating MMP expression.…”

Section: Discussionsupporting

confidence: 92%

Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation

Orbe

Rodríguez

Calvayrac

et al. 2009

ATVB

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Objective-Thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. Methods and Results-Thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated receptor-1 (PAR-1)-dependent mechanism, in a dose-and time-dependent manner. This effect was mimicked by a PAR-1 agonist peptide (TRAP-1) and antagonized by an anti-PAR-1 blocking antibody. MMP-10 induction was dependent on extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways. By serial deletion analysis, site-directed mutagenesis and electrophoretic mobility shift assay an AP-1 site in the proximal region of MMP-10 promoter was found to be critical for thrombin-induced MMP-10 transcriptional activity. Thrombin and TRAP-1 upregulated MMP-10 in murine endothelial cells in culture and in vivo in mouse aorta. This effect of thrombin was not observed in PAR-1-deficient mice. Interestingly, circulating MMP-10 levels (PϽ0.01) were augmented in patients with endothelial activation associated with high (disseminated intravascular coagulation) and moderate (previous acute myocardial infarction) systemic thrombin generation. Conclusion-Thrombin induces MMP-10 through a PAR-1-dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation. Key Words: thrombin Ⅲ endothelium Ⅲ MMP-10 Ⅲ atherosclerosis Ⅲ thrombosis T here is growing evidence for an intimate link between inflammatory and coagulation pathways in vascular disease. Inflammation appears to shift the hemostatic mechanisms in favor of thrombosis, and conversely, coagulation pathways influence inflammatory response. [1][2][3] Thrombin participates in this interplay and, besides its well established role in thrombosis and hemostasis, activates protease-activated receptors (PARs) and elicits multiple effects in a variety of cell types. 1 PARs have been implicated in the control of vascular tone, vascular permeability, and secretory activity of endothelial cells. 4 -6 In addition, the activation of PARs induces the production of proinflammatory cytokines, upregulates cell adhesion molecules, and promotes leukocyte rolling in different models. 7-9 PAR-1 seems to be the major mediator of thrombin signaling in vascular endothelial cells (ECs) in mice and humans, and most of the actions of thrombin on ECs have been reproduced using the PAR-1 agonist peptides. 10 Thrombin exerts powerful proinflammatory effects on vascular cells and upregulates some matrix degrading metalloproteinases (MMPs). [11][12][13] MMPs are zinc-dependent endopeptidases capable of degrading extracellular matrix (ECM) proteins, but also process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptoti...

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Section: Discussionsupporting

confidence: 92%

Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation

Orbe

Rodríguez

Calvayrac

et al. 2009

ATVB

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“…MMP-9 acts synergistically with thrombin to exacerbate ICH injury [19]. Brain microvascular endothelial cells (BMECs) and astrocytes release MMP-9 due to thrombin stimulation [20,21]. Wang et al elucidated the localization of active MMP-9 in the various types of cells including neurons, astrocytes, neutrophils, microglia/macrophages, and endothelial cells [18].…”

Section: Introductionmentioning

confidence: 98%

Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood–brain barrier in vitro

Machida

Takata

Matsumoto

et al. 2015

Neuroscience Letters

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“…In addition to its hemostatic roles, thrombin modulates a diversity of pathophysiological functions such as inflammation, cell migration and proliferation, apoptosis and so on. There are many evidences that thrombin regulates MMP-9 expression [6][7][8] and cancer cell migration [9][10][11]. Nevertheless, the effect of thrombin on glioma cell migration is not fully understood even though thrombin released by hemorrhagic site of GBM may have a important role in invasion.…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Lee

Kim

et al. 2011

Korean J Physiol Pharmacol

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ABBREVIATIONS: MMP-9, matrix metalloproteinase-9; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase.Received June 7, 2011, Revised August 16, 2011, Accepted August 28, 2011 Corresponding to: Sung-Soo Kim, Department of Pharmacology, College of Medicine, Kangwon National University, Hyoja-2-dong, (Fax) 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 W estern 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.

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Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes

Cited by 40 publications

References 51 publications

Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation

Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation

Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood–brain barrier in vitro

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

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