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PubMed2006

Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex.

Results of previous studies suggested a role of mitochondria in intracellular and cell-cell lactate shuttles. Therefore, by using a rat-derived L6 skeletal muscle cell line and confocal laser-scanning microscopy (CLSM), we examined the cellular locations of mitochondria, lactate dehydrogenase (LDH), the lactate-pyruvate transporter MCT1, and CD147, a purported chaperone protein for MCT1. CLSM showed that LDH, MCT1, and CD147 are colocalized with the mitochondrial reticulum. Western blots showed that cytochrome oxidase (COX), NADH dehydrogenase, LDH, MCT1, and CD147 are abundant in mitochondrial fractions of L6 cells. Interactions among COX, MCT1, and CD147 in mitochondria were confirmed by immunoblotting after immunoprecipitation. These findings support the presence of a mitochondrial lactate oxidation complex associated with the COX end of the electron transport chain that might explain the oxidative catabolism of lactate and, hence, mechanism of the intracellular lactate shuttle.

Animals↗
PubMed2002

Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.

High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.

Antigens, CD↗
PubMed2005

Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases.

Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.

Animals↗
PubMed2006

A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness, and metastatic activity of malignant melanoma.

CD147 plays a critical role in the invasive and metastatic activity of malignant melanoma cells by stimulating the surrounding fibroblasts to express matrix metalloproteinases and vascular endothelial growth factor. We developed a system that blocks CD147 in the human malignant melanoma cell line, A375, using RNA interference. By transfecting melanoma cells with the small interfering RNA (siRNA) that targets human CD147, we were able to establish two stable clones in which CD147 expression was significantly down-regulated. This resulted in the decreased proliferation and invasion of A375 cells in vitro. CD147 siRNA also down-regulated the expression of vascular endothelial growth factor in these cells and reduced the migration of vascular endothelial cells. The reduction in the CD147 level suppressed the size of s.c. tumors and the microvessel density in an A375 s.c. nude mouse xenograft model. In addition, the in vivo metastatic potential of A375 cells transfected with CD147 siRNA was suppressed in a nude mouse model of pulmonary metastasis.

Animals↗
PubMed2007

Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer.

Animals↗
PubMed2004

Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells.

PURPOSE: EMMPRIN (extracellular matrix metalloprotease inducer) is a glycosylated member of the immunoglobulin superfamily known to stimulate the production of matrix metalloproteases (MMPs) 1, 2, and 3 and MT1-MMP in peritumoral fibroblasts. We here evaluated whether EMMPRIN expression is related to tumor progression in human breast cancer. EXPERIMENTAL DESIGN: An immunohistochemical study using high-density tissue microarrays (n = 2222 breast cancer samples) and EMMPRIN-specific antibodies HIM6 and MEM-M6/1 was performed, and staining results were statistically correlated with various clinicopathological parameters. To analyze the putative association between EMMPRIN expression and bone marrow (BM) micrometastasis, an additional set of 55 breast tumors from patients with or without micrometastatic cells as determined with anti-cytokeratin antibody A45-B/B3 were included in our study. Cytokeratin-positive cells in BM were costained with EMMPRIN-specific antibody 1G6.2. RESULTS: Positive EMMPRIN staining correlated significantly with various histopathological risk factors (higher tumor grade, increased tumor size, negative estrogen receptor status and progesterone receptor status, and higher mitotic index) as well as decreased tumor-specific survival (log-rank, P = 0.0027). In particular, in patients > 50 years (i.e., postmenopausal women), EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (relative risk = 1.7, 95% confidence interval 1.4-4.3, P = 0.036). An involvement of EMMPRIN in tumor progression was also supported by the fact that it was expressed on approximately 90% of micrometastatic cells in BM. CONCLUSIONS: EMMPRIN expression in primary tumor predicts an unfavorable prognosis in breast cancer, suggesting a crucial role of EMMPRIN in progression of human mammary carcinomas.

Antigens, CD↗
PubMed2005

Extracellular matrix metalloprotease inducer-expressing head and neck squamous cell carcinoma cells promote fibroblast-mediated type I collagen degradation in vitro.

Until recently, tumor progression has been considered a multistep process defined by tumor cell mutations and the importance of the surrounding stroma poorly understood. It is now recognized that matrix-degrading enzymes that promote tumor cell invasion are elaborated by both tumor cells and fibroblasts in vivo. To determine the relative role of tumor cell-derived proteases compared with fibroblast-derived proteases, coculture experiments were done with each cell type using an in vitro model of type I collagen degradation. Head and neck squamous cell carcinoma cells in coculture with normal dermal fibroblasts showed matrix degradation, but neither cell type alone produced this effect. Manipulating the in vitro coculture environment showed that collagenolysis in this model was a result of fibroblast-derived matrix metalloproteases (MMP). To explore the possible role of extracellular matrix metalloprotease inducer (EMMPRIN) in this interaction, transfection of EMMPRIN into a cell line with low endogenous EMMPRIN expression was done and showed a significant increase in collagenolysis. Inhibition of collagenolysis with a tissue inhibitor of metalloprotease-2 (TIMP-2) and a synthetic furin inhibitor was observed but not with TIMP-1, which suggested a possible role for membrane type-1 MMP. These results suggest that fibroblast-derived MMPs but not those from tumor cells are important for in vitro collagenolysis and that this process is promoted by tumor cell-expressed EMMPRIN.

Antigens, CD↗
PubMed2006

Regulation of vascular endothelial growth factor expression by EMMPRIN via the PI3K-Akt signaling pathway.

Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) is a cell surface glycoprotein overexpressed in many solid tumors. In addition to its ability to stimulate stromal MMP expression, tumor-associated EMMPRIN also induces vascular endothelial growth factor (VEGF) expression. To explore the underlying signaling pathways used by EMMPRIN, we studied the involvement of phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), JUN, and p38 kinases in EMMPRIN-mediated VEGF regulation. Overexpression of EMMPRIN in MDA-MB-231 breast cancer cells stimulated the phosphorylation of only Akt and MAPKs but not that of JUN and p38 kinases. Conversely, inhibition of EMMPRIN expression resulted in suppressed Akt and MAPK phosphorylation. Furthermore, the PI3K-specific inhibitor LY294002 inhibited VEGF production by EMMPRIN-overexpressing cells in a dose- and time-dependent manner. On the other hand, the MAPK inhibitor U0126 did not affect VEGF production. In vivo, EMMPRIN-overexpressing tumors with elevated VEGF expression had a high level of phosphorylation of Akt and MAPK. Finally, when fibroblast cells were treated with recombinant EMMPRIN, Akt kinase but not MAPK was phosphorylated concomitant with an increase in VEGF production. Both the activation of Akt kinase and the induction of VEGF were specifically inhibited with a neutralizing antibody to EMMPRIN. Our results show that in both tumor and fibroblast cells EMMPRIN regulates VEGF production via the PI3K-Akt pathway but not via the MAPK, JUN, or p38 kinase pathways.

Animals↗
PubMed1999

Activation of microglia during developmentally regulated cell death in the cerebral cortex.

Neuronal elimination in the developing CNS is accomplished by an orderly type of cellular suicide called programmed cell death. The principal non-neuronal cells implicated in regulating programmed cell death and subsequent phagocytosis of dying neurons are the brain's macrophage population, the microglia. Little is known about the signaling between microglia and neurons during programmed cell death. However, macrophages in non-neural tissues express receptors for immunoglobulin (IgG) and complement, and these molecules help regulate phagocytosis of dying cells and foreign organisms. Since many of the neurons generated early in CNS development are transient cell types that are immunoreactive for IgG [Upender et al.: J Comp Neurol 1997; 384:271-282], we hypothesized that IgG might alter the phagocytic properties of microglia within the developing nervous system and potentiate engulfment of dying cells. To begin to address this hypothesis, we first asked whether cortical neurons immunoreactive for IgG or calbindin-D28k exhibit morphological evidence of programmed cell death in the cerebral cortex of neonatal rat pups. Secondly, we quantified the incidence of contacts made by microglia on IgG- vs. calbindin-immunoreactive neurons. Thirdly, perturbation experiments were performed to elevate intracortical levels of IgG and the incidence of microglia:neuron contacts were determined. We found that although the nuclei of some IgG-immunoreactive neurons exhibited condensation and fragmentation characteristic of programmed cell death, we did not observe pyknotic calbindin-immunoreactive neurons. IgG-immunoreactive neurons were also more likely to be contacted by microglia than calbindin-immunoreactive neurons. Elevating intracortical levels of IgG experimentally led to a dramatic increase in the expression of microglia complement receptors throughout the cerebral cortex. Taken together, these results suggest that IgG normally present within neuronal subsets in the developing cerebral cortex could serve to locally regulate the expression of complement receptors on microglia.

Animals↗
PubMedDate not supplied

Neural stem cells in the subventricular zone are a source of astrocytes and oligodendrocytes, but not microglia.

The developmental origin of microglia remains a controversial subject. While it is generally accepted that primitive fetal macrophages that migrate from the yolk sac to the brain become microglia, it also has been argued that there is a second source of microglia that are of neuroectodermal lineage. To determine whether progenitors in the dorsolateral subventricular zone (SVZDL) are capable of producing microglia as well as macroglia, we infected perinatal rat SVZDL cells with a mixture of two replication-deficient retroviruses, placed these progenitors in vitro and then varied the media formulations to promote microglial differentiation. Mixed macroglial clones were obtained, but no heterogeneous clones containing microglia were observed, regardless of the media components. Among the macroglial clones, we observed every possible combination of type 1 astrocyte and O-2A lineage cells. Some clones were homogeneous and contained cells belonging to a single macroglial lineage. Other clonal clusters were heterogeneous and were comprised of type 1 astrocytes and oligodendrocytes, type 1 and type 2 astrocytes, or type 2 astrocytes and oligodendrocytes. Of 130 clones examined, where we used triple immunofluorescence with antibodies that recognize microglia, 2 clonal clusters contained OX-42+ microglia that were retrovirally labeled, but all of the cells in those clones expressed the microglial marker and none expressed either GFAP or O4. In addition, we isolated neural stem cells from the perinatal SVZDL and assessed their capacity to generate macroglia and microglia. Confirming and extending our previous analyses, neural stem cells generated homogeneous and heterogeneous macroglial clones, but they did not generate microglia. We conclude that brain macroglia and microglia do not share a common precursor, even though the neural stem cells in the SVZDL cells can produce neurons, astrocytes and oligodendrocytes. Therefore, the microglia that reside in the SVZDL are immigrants from nonneural precursors.

Animals↗
PubMed2004

5A11/Basigin gene products are necessary for proper maturation and function of the retina.

5A11/Basigin gene products are important membrane glycoproteins for development and maturation of the retina. The gene encodes two immunoglobulin-like, membrane-bound glycoproteins as a result of splice variation. The smaller protein product, named 5A11/Basigin, is expressed by many tissues within the mouse, whereas the larger protein product, named 5A11/Basigin-2, is expressed only by the photoreceptor cells (PCs) of the retina. Mice in which the gene for 5A11/Basigin has been deleted have several abnormalities, including blindness from the time of eye opening with subsequent degeneration of the PCs. Studies by this laboratory suggest that a developmental deficiency is the underlying cause of the blindness. However, definitive biological functions for 5A11/Basigin and 5A11/Basigin-2 have yet to be defined. It is known that 5A11/Basigin is multifunctional and can interact with several different proteins. Preliminary studies indicate that 5A11/Basigin-2 may be multifunctional as well. Studies by this laboratory and others have demonstrated that 5A11/Basigin (and probably 5A11/Basigin-2) acts as a chaperone for monocarboxylate transporter-1 (MCT-1) translocation to the cell membrane. We have proposed that a lactate metabolon exists within the retina and functions to shuttle lactate, an energy source, from glial cells to the PCs. This metabolon is not present within 5A11/Basigin null mouse retinas, which may be the underlying cause of the retinal dysfunction and subsequent degeneration. Further studies will be necessary to determine which of the functions are critical for proper development of the retina.

Animals↗
PubMed1992

Tumor collagenase-stimulating factor and tumor autocrine motility factor as tumor markers in bladder cancer--an update.

We have studied the role of combined measurements of tumor collagenase-stimulating factor (TCSF) and tumor autocrine motility factor (TAMF) in 83 first morning voids and 24-hour specimens in patients with bladder and renal cancer and control subjects. TCSF and TAMF were measured by immunoabsorption assay and motility test utilizing modified Boyden chamber. The mean concentrations of urinary TCSF and TAMF from cancer patients (n = 32) were 4- to 5-fold higher than those from benign conditions (n = 70). We compared TCSF and TAMF utilizing motility test in first morning voids (n = 18) and 24-hour urinary samples (n = 19). TCSF and TAMF were almost identical in terms of eluted proteins from morning voids and 24-hour urine samples. Invasive bladder cancer (n = 12) showed a significantly higher correlation (r = 0.9 and p = 0.0001) between motility response and urinary concentration of TCSF and TAMF. We have also localized these two glycoproteins in cell membranes and cytoplasms of cancer cell.

Antigens, CD↗
PubMed2002

Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma.

OBJECTIVE: Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell-derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)-differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma. METHODS AND RESULTS: After 10 days of GM-CSF-induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF-differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF-differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions. CONCLUSIONS: Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.

Adult↗
PubMed2004

Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase Inducer (EMMPRIN) release by coronary smooth muscle cells.

OBJECTIVE: Matrix metalloproteinases (MMPs) seem to play a prominent role in atherogenesis. Extracellular MMP inducer (EMMPRIN), a cell surface glycoprotein which stimulates MMP synthesis, has recently been detected in human atheroma. We have investigated the influence of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs). METHODS AND RESULTS: OxLDL induced a significant increase of EMMPRIN release into HCA-SMC supernatants and a concomitant decrease of cell-associated EMMPRIN. These effects were antagonized by antioxidants as well as by EDTA and the MMP inhibitor GM6001. Western blot analysis demonstrated that MMP-1 and MMP-2 induce the cleavage of the extracellular domain from cell-associated EMMPRIN. MMP-1 and MMP-2 synthesis was upregulated by oxLDL, and, in addition, we have shown that soluble EMMPRIN, isolated from macrophage supernatants, increased MMP-1 and MMP-2 synthesis in HCA-SMC. CONCLUSIONS: Our data suggest that oxLDLs stimulate the release of soluble EMMPRIN, at least in part, by MMP-dependent shedding from the cell surface. Additionally, oxLDLs might induce a circular upregulation of matrix degradation because, in turn, soluble EMMPRIN stimulates MMP synthesis in HCA-SMC.

Antigens, CD↗
PubMed2000

A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure.

BACKGROUND: Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to increase MMP expression, and membrane-type MMP or MT1-MMP has been implicated to activate MMPs. The present study examined whether and to what degree EMMPRIN and MT1-MMP were expressed in human left ventricular (LV) myocardium as well as the association with MMP activity and expression in dilated cardiomyopathy (DCM). METHODS AND RESULTS: LV myocardial zymographic MMP activity increased by >2-fold with both nonischemic DCM (n=21) and ischemic DCM (n=16) compared with normal (n=13). LV myocardial abundance of MMP-9 was increased with both forms of DCM. MMP-2 and MMP-3 were increased with nonischemic DCM. MMP-1 levels were decreased with both forms of DCM. EMMPRIN increased by >250% and MT1-MMP increased by >1000% with both forms of DCM. CONCLUSIONS: Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred. Moreover, a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM. The control of MMP activation and expression in the failing human LV myocardium represents a new and potentially significant therapeutic target for this disease process.

Adolescent↗
PubMed2005

Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms.

BACKGROUND AND PURPOSE: We studied matrix metalloproteinases (MMP) 2, 8, and 9 and extracellular matrix metalloproteinase inducer (EMMPRIN) levels in relation to carotid atherosclerotic plaque characteristics. METHODS: Carotid atherosclerotic plaques (n=150) were stained and analyzed for the presence of collagen, smooth muscle cell (SMC), and macrophages. Adjacent segments were used to isolate total protein to assess MMP-2 and MMP-9 activities and gelatin breakdown, MMP-8 activity, and EMMPRIN levels. RESULTS: Macrophage-rich lesions revealed higher MMP-8 and MMP-9 activities, whereas SMC-rich lesions showed higher MMP-2 activity. The levels of less glycosylated EMMPRIN-45kD were higher in SMC-rich lesions and lower in macrophage-rich plaques. EMMPRIN-45kD was associated with MMP-2 levels, whereas EMMPRIN-58kD was related to MMP-9 levels. CONCLUSIONS: MMP-2, MMP-8, and MMP-9 activities differed among carotid plaque phenotypes. Different EMMPRIN glycosylation forms are associated with either MMP-2 or MMP-9 activity, which suggests that EMMPRIN glycosylation may play a role in MMP regulation and plaque destabilization.

Analysis of Variance↗
PubMed2006

Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction.

BACKGROUND: Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in MMP synthesis by as yet unknown mechanisms. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro has not yet been studied. Thus, we studied EMMPRIN expression on monocytes in acute myocardial infarction (MI) and its potential relevance for MMP activation. METHODS AND RESULTS: In 20 patients with acute MI, surface expression of EMMPRIN was significantly enhanced on monocytes compared with in 20 patients with chronic stable angina. EMMPRIN upregulation was associated with increased expression of the membrane type 1 MMP (MT1-MMP) on monocytes (flow cytometry) as well as MMP-9 activity (gelatin zymography) in the plasma. At 6 months after successful revascularization, EMMPRIN, MT1-MMP, and MMP-9 had normalized. The secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese hamster ovary cells. Moreover, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells. Gene silencing of EMMPRIN by small-interfering RNA hindered lipopolysaccharide-induced monocyte secretion of MMP-9, indicating a predominant role of EMMPRIN in MMP-9 induction. CONCLUSIONS: EMMPRIN and MT1-MMP are upregulated on monocytes in acute MI. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in smooth muscle cells, indicating that EMMPRIN may display a key regulatory role for MMP activity in cardiovascular pathologies.

Adult↗
PubMed2001

Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).

Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.

ADAM Proteins↗