Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases degrade the extracellular matrix and are involved in a variety of diseases, including inflammatory diseases of the central nervous system. Here we estimated the content of gelatinase in rat brain under control conditions and 4 h after transient focal ischemia using gelatinolytic extraction and zymographic analysis. We also examined the expression of the MMP-9 and MMP-2 proteins by Western blot. Using the zymographic apparent gelatinase activity we estimated that brain gelatinase content was 0.44 ng/mg of protein. Ischemia induced a 1.7-fold increase at 4 h, thus showing an early MMP response to the ischemic injury. The main increase was seen for the MMP-9 proform, which was accompanied by enhanced MMP-9 protein expression. We suggest that basal cerebral MMP-9 and MMP-2 activities are involved in the maintenance of the extracellular matrix and prevent substrate accumulation, while enhanced postischemic MMP activity before cell death may contribute to edema formation and blood-brain barrier breakdown.
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PMID:Estimation of gelatinase content in rat brain: effect of focal ischemia. 1109 88

Deleterious processes of extracellular proteolysis may contribute to the progression of tissue damage after acute brain injury. We recently showed that matrix metalloproteinase-9 (MMP-9) knock-out mice were protected against ischemic and traumatic brain injury. In this study, we examined the mechanisms involved by focusing on relevant MMP-9 substrates in blood-brain barrier, matrix, and white matter. MMP-9 knock-out and wild-type mice were subjected to transient focal ischemia. MMP-9 levels increased after ischemia in wild-type brain, with expression primarily present in vascular endothelium. Western blots showed that the blood-brain barrier-associated protein and MMP-9 substrate zonae occludens-1 was degraded after ischemia, but this was reduced in knock-out mice. There were no detectable changes in another blood-brain barrier-associated protein, occludin. Correspondingly, blood-brain barrier disruption assessed via Evans Blue leakage was significantly attenuated in MMP-9 knock-out mice compared with wild types. In white matter, ischemic degradation of the MMP-9 substrate myelin basic protein was significantly reduced in knock-out mice compared with wild types, whereas there was no degradation of other myelin proteins that are not MMP substrates (proteolipid protein and DM20). There were no detectable changes in the ubiquitous structural protein actin or the extracellular matrix protein laminin. Finally, 24 hr lesion volumes were significantly reduced in knock-out mice compared with wild types. These data demonstrate that the protective effects of MMP-9 gene knock-out after transient focal ischemia may be mediated by reduced proteolytic degradation of critical blood-brain barrier and white matter components.
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PMID:Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. 1156 62

Spatial and temporal relations between metalloproteinase (MMP-2 and MMP-9) activation and laminin degradation in gerbil hippocampus after transient cerebral ischemia has been studied. Activity of MMPs was determined by gelatin zymography in homogenates from dorsal (DP, an equivalent of CA1 sector) and abdominal (AbP, containing CA2-4 and gyrus dentatus) parts of hippocampus. A significant activation of both investigated metalloproteinases was found at 72 h of recovery. Whereas MMP-2 up-regulation did not show any spatial preferences, the increase of MMP-9 activity was observed exclusively in DP. Activation of MMP-9 at this time point correlated spatially with degradation of laminin-protein of extracellular matrix. These results show that MMP pathway may function as a component of delayed neuronal death cascade in the apoptogenic CA1 sector after transient global ischemia.
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PMID:Involvement of MMPs in delayed neuronal death after global ischemia. 1220 Oct 33

Angiogenesis, an essential component of a variety of physiological and pathological processes, offers attractive opportunities for therapeutic regulation. We hypothesized that matrix metalloproteinase-9 genetic deficiency (MMP-9-/-) will impair angiogenesis triggered by tissue ischemia, induced experimentally by femoral artery ligation in mice. To investigate the role of MMP-9, we performed a series of biochemical and histological analyses, including zymography, simultaneous detection of perfused capillaries, MMP-9 promoter activity, MMP-9 protein, and macrophages in MMP-9-/- and wild-type (WT) mice. We found that ischemia resulted in doubling of capillary density in WT and no change in the MMP-9-/- ischemic tissues, which translated into increased (39%) perfusion capacity only in the WT at 14 days after ligation. We also confirmed that capillaries in the MMP-9-/- presented significantly (P<0.05) less points of capillary intersections, interpreted by us as decreased branching. The combined conclusions from simultaneous localizations of MMP-9 expression, capillaries, and macrophages suggested that macrophage MMP-9 participates in capillary branching. Transplantation of WT bone marrow into the MMP-9-/-, restored capillary branching, further supporting the contribution of bone marrow-derived macrophages in supplying the necessary MMP-9. Our study indicates that angiogenesis triggered by tissue ischemia requires MMP-9, which may be involved in capillary branching, a potential novel role for this MMP that could be exploited to control angiogenesis.
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PMID:Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. 1476 48

Chronic limb-threatening ischemia is a devastating disease with limited surgical options. However, inducing controlled angiogenesis and enhancing reperfusion holds therapeutic promise. To gain a better understanding of the mechanisms that contribute to limb reperfusion, we examined the temporal biochemical and structural changes occurring within the extracellular matrix of ischemic skeletal muscle. Both the latent and active forms of MMP-2 and -9 significantly increased during the active phase of limb reperfusion. Moreover, small but significant alterations in tissue inhibitors of metalloproteinase levels also occurred during a similar time course, consistent with a net increase in extracellular matrix remodeling. This temporal increase in MMP activity coincided with enhanced exposure of the unique HU177 cryptic collagen epitope. Although the HUIV26 cryptic collagen epitope has been implicated in angiogenesis, little is known concerning such epitopes within ischemic muscle tissue. Here, we provide the first evidence that a functionally distinct cryptic collagen epitope (HU177) is temporally exposed in ischemic muscle tissue during the active phase of reperfusion. Interestingly, the exposure of the HU177 epitope was greatly diminished in MMP-9 null mice, corresponding with significantly reduced limb reperfusion. Therefore, the regulated exposure of a unique cryptic collagen epitope within ischemic muscle suggests an important role for collagen remodeling during the active phase of ischemic limb reperfusion.
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PMID:Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion. 1625 19

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
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PMID:Microglial activation and matrix protease generation during focal cerebral ischemia. 1726 8

Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.
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PMID:Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia. 1839 9

Hippocampal neuronal death following transient global ischemia in the mouse takes days to occur, providing a potential timeframe for therapeutic intervention. Since matrix metalloproteinase-3 (MMP-3) enhances inflammation and tissue inhibitor of metalloproteinases-3 (TIMP-3) promotes apoptosis in ischemia, we hypothesized that they are involved in neuronal death secondary to transient global ischemia. Timp-3 knockout (T3KO) and wild type (T3WT) mice underwent 30 min bilateral carotid artery occlusion (BCAO), which causes hippocampal neuronal death 7 days after reperfusion. Mice lacking the Timp-3 gene have significantly less astrocytosis, microglial reactivity, MMP-3 activity and neuronal cell death. In addition, T3KO mice had decreased tumor necrosis factor (TNF) receptor-1 (TNFR1) expression and increased TNF-alpha converting enzyme (TACE) activity. Mmp-3 KO mice with a similar BCAO showed significantly fewer microglial cells, reduced TNF-alpha expression, and less neuronal death than the Mmp-3 WT. To see if TIMP-3 and MMP-3 cell death pathways were independent, we blocked MMPs with the broad-spectrum MMP inhibitor, BB-94, on days 3 through 6 of reperfusion in T3WT and T3KO mice. BB-94 rescued hippocampal neurons at 7 days in both T3WT and T3KO mice, but significantly fewer neurons died in T3KO mice treated with BB-94. Our results indicate a novel additive role for TIMP-3 and MMP-3 in delayed neuronal death, and show that delayed treatment with MMP inhibitors can be used to reduce hippocampal death.
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PMID:TIMP-3 and MMP-3 contribute to delayed inflammation and hippocampal neuronal death following global ischemia. 1911 39

PURPOSE. The pathogenesis of retinal ischemia results from a series of events involving changes in gene expression and inflammatory cytokines. Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. The purpose of this study was to investigate the neuroprotective action of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in a retinal ischemic model. METHODS. To investigate whether HDAC inhibition can reduce ischemic injury, rats were treated with TSA (2.5 mg/kg intraperitoneally) twice daily on days 0, 1, 2, and 3. Seven days after ischemic injury, morphometric and electroretinographic (ERG) analyses were used to assess retinal structure and function. Western blot and immunohistochemical analyses were used to evaluate TSA-induced changes in histone-H3 acetylation and MMP secretion. RESULTS. In vehicle-treated animals, ERG a- and b-waves from ischemic eyes were significantly reduced compared with contralateral responses. In addition, histologic examination of these eyes revealed significant degeneration of inner retinal layers. In rats treated with TSA, amplitudes of ERG a- and b-waves from ischemic eyes were significantly increased, and normal inner retina morphology was preserved. Ischemia also increased the levels of retinal TNF-alpha, which was blocked by TSA treatment. In astrocyte cultures, the addition of TNF-alpha (10 ng/mL) stimulated the secretion of MMP-1 and MMP-3, which were blocked by TSA (100 nM). CONCLUSIONS. These studies provide the first evidence that suppressing HDAC activity can protect the retina from ischemic injury. This neuroprotective response is associated with the suppression of retinal TNF-alpha expression and signaling. The use of HDAC inhibitors may provide a novel treatment for ischemic retinal injury.
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PMID:Inhibition of histone deacetylase protects the retina from ischemic injury. 2016 49

We have shown that melatonin attenuated matrix metalloproteinase-9 (MMP-9) activation and decreased the risk of hemorrhagic transformation following cerebral ischemia-reperfusion. Herein, we investigate the possible involvement of the plasminogen/plasmin system and endogenous MMPs inhibitor underlying the melatonin-mediated MMP-9 inhibition. Mice were subjected to 1-hr ischemia and 48-hr reperfusion of the right middle cerebral artery. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhagic transformation were measured. Extracellular matrix damage was determined by Western immunoblot analysis for laminin protein. The activity and expression of MMP-2 and MMP-9 were determined by gelatin zymography, in situ zymography, and Western immunoblot analysis. In addition, the activities of tissue and urokinase plasminogen activators (tPA and uPA) were evaluated by plasminogen-dependent casein zymography. Endogenous plasminogen activator inhibitor (PAI) and tissue inhibitors of MMP (TIMP-1) were investigated using enzyme-linked immunosorbent assay (ELISA) and Western immunoblot analysis, respectively. Cerebral ischemia-reperfusion induced increased MMP-9 activity and expression at 12-48 hr after reperfusion onset. Relative to controls, melatonin-treated animals had significantly decreased MMP-9 activity and expression (P<0.05), in addition to reduced brain infarction and hemorrhagic transformation as well as improved laminin protein preservation. This melatonin-mediated MMP-9 inhibition was accompanied by reduced uPA activity (P<0.05), as well as increased TIMP-1 expression and PAI activity (P<0.05, respectively). These results demonstrate the melatonin's pluripotent mechanisms for attenuating postischemic MMP-9 activation and neurovascular damage, and further support it as an add-on to thrombolytic therapy for ischemic stroke patients.
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PMID:Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. 2066 46


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