Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Mechanisms of selective neuronal death in the hippocampus after global cerebral ischemia remain to be clarified. Here, we explored a possible role for matrix metalloproteinases (MMPs) in this phenomenon. Although many studies have demonstrated detrimental roles for the gelatinase MMP-9 in focal cerebral ischemia, how dysregulated MMP proteolysis influences global cerebral ischemia is less well understood. In this study, CD-1 mice were subjected to transient global ischemia. Transient occlusions of common carotid arteries for periods between 20 and 40 min led to increasing hippocampal neuronal death after 3 d. Gel zymography showed elevations in gelatinase (MMP-2 and MMP-9) activity. In situ zymography showed that gelatinase activity was mostly colocalized with neuron-specific nuclear protein-stained pyramidal neurons. Mice treated with the broad-spectrum metalloproteinase inhibitor BB-94 (50 mg/kg, i.p.) showed reduced hippocampal gelatinase activity after transient global cerebral ischemia and suffered significantly reduced hippocampal neuronal damage compared with vehicle-treated controls (p < 0.01). Additionally, hippocampal gelatinase activity and neuronal damage after transient global ischemia were also significantly reduced in MMP-9 knock-out mice compared with wild-type mice (p < 0.05). These data indicate a potential deleterious role for MMP-9 in the pathogenesis of delayed neuronal damage in the hippocampus after global cerebral ischemia.
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PMID:Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. 1473 53

Uncontrolled activation of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation, yet little is known about the activation of MMPs during orthotopic liver transplantation (OLT). OLT is associated with increased fibrinolytic activity due to elevated plasmin generation. The serine-protease plasmin not only causes degradation of fibrin clots but is also thought, amongst others, to play a role in the activation of some matrix metalloproteinases. We therefore studied the evolution of MMP-2 and -9 plasma concentrations during OLT and the effect of serine-protease inhibition by aprotinin on the level and activation of these MMPs. In a group of 24 patients who participated in a randomized, double-blind, placebo-controlled study we determined serial MMP-2 and MMP-9 plasma levels during transplantation using ELISA (total MMP), activity assays (activatable MMP) and zymography. In addition, the MMP-inhibitors TIMP-1 and TIMP-2 were assessed by ELISA. The putative regulating factors tumor necrosis factor alpha (TNF-alpha) and tissue-type plasminogen activator (t-PA) were assessed as well. Patients were administered high-dose aprotinin, regular-dose aprotinin or placebo during surgery. Plasma TIMP-1, TIMP-2 and MMP-2 level gradually decreased during transplantation. Approximately two-thirds of total MMP-2 appeared to be in its activatable proMMP form. No release of MMP-2 from the graft could be detected. In contrast, plasma levels of MMP-9 increased sharply during the anhepatic and postreperfusion periods. Peak MMP-9 levels of about eight times above baseline were found at 30 minutes after reperfusion. Most MMP-9 appeared to be in its active/inhibitor-complexed form. No significant differences were observed between the three treatment groups. However, in patients with more severe ischemia/reperfusion (I/R) injury the MMP-9 concentration, particularly of the active/inhibitor-complexed form, remained high at 120 minutes postreperfusion compared to patients with no or mild I/R injury. The decrease in plasma levels of MMP-2, TIMP-1 and TIMP-2 during OLT occurred irrespective of the severity of the I/R injury. There was a significant correlation between MMP-9 and t-PA levels, but not with TNF-alpha. In conclusion, OLT is associated with a sharp increase of MMP-9 during the anhepatic and postreperfusion periods, which coincided with the changes in t-PA. MMP-2, TIMP-1 and TIMP-2 gradually decreased during OLT. The composition of these MMPs was not altered by the use of aprotinin, suggesting that serine-protease/plasmin-independent pathways are responsible for MMP regulation during OLT. In addition, only MMP-9 seems to be involved in I/R injury during human liver transplantation.
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PMID:Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation. The effect of aprotinin and the relation to ischemia/reperfusion injury. 1498 26

Ischemic injury to the kidney results in blood vessel loss and predisposition to chronic renal disease. Angiostatin is a proteolytic cleavage product of plasminogen that inhibits angiogenesis, promotes apoptosis of endothelial cells, and disrupts capillary integrity. A combination of lysine-Sepharose enrichment followed by Western blotting was used to study the expression of angiostatin in response to the induction of ischemic renal injury. No angiostatin products were readily detectable in kidneys of sham-operated control rats. In contrast, both 38- and 50-kDa forms of angiostatin were dramatically enhanced in the first 3 days following 45-min ischemia-reperfusion injury. Renal angiostatin levels declined but remained detectable at late time points postrecovery (8-35 days postischemia). Angiostatin-like immunoreactivity was also elevated in the plasma and in urine for up to 35 days following injury. Lysine-Sepharose extracts of either kidney or urine inhibited vascular endothelial cell growth factor-induced proliferation of human aortic endothelial cells in vitro; an effect that was blocked by coincubation with an angiostatin antibody. RT-PCR verified that mRNA of the parent protein plasminogen was produced in the liver, but it was not present in either sham-operated or postischemic kidney. Matrix metalloproteinase (MMP)-2 and MMP-9, which may mediate angiostatin generation, were enhanced in postischemic kidney tissue and were localized to the renal tubules, interstitial cells, and the tubulo-interstitial space. These data indicate the possible local synthesis of angiostatin following acute renal failure (ARF) and suggest a possible role for MMPs in this activity. Renal angiostatin generation following ARF may modulate renal capillary density postischemia and thereby influence chronic renal function.
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PMID:Angiostatin and matrix metalloprotease expression following ischemic acute renal failure. 1507 85

The 70 kDa heat shock protein (Hsp70) is synthesized in response to a variety of stresses, including ischemia, and is thought to act as a molecular chaperone to prevent protein denaturation and facilitate protein folding. Matrix metalloproteinases (MMPs), a family of serine proteases, are also upregulated by ischemia and are thought to promote cell death and tissue injury. We examined the influence of Hsp70 on expression and activity of MMPs. Astrocyte cultures were prepared from neonatal mice and transfected with retroviral vectors containing hsp70 or lacZ or mock infected, then exposed to oxygen-glucose deprivation followed by reperfusion. Zymograms and Western blots showed that Hsp70 over-expression suppressed MMP-2 and MMP-9. These findings suggest that Hsp70 may protect by regulating MMPs.
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PMID:The 70 kDa heat shock protein suppresses matrix metalloproteinases in astrocytes. 1509 11

Tetracyclines exhibit significant anti-inflammatory properties, inhibit matrix metalloproteinases (MMPs), and are protective in models of ischemia-reperfusion injury (IRI). Both inflammatory cascades and MMP activation have been demonstrated to modulate microvascular permeability. Because increased microvascular permeability occurs during IRI in a variety of organ systems including the kidney, we hypothesized that minocycline, a semisynthetic tetracycline, would diminish microvascular leakage during renal IRI. To test this hypothesis, we used intravital 2-photon microscopy to examine leakage of fluorescent dextrans from the vasculature in a rodent model of IRI. Minocycline significantly reduced the extent of dextran (500 kDa) leakage from the renal microvasculature 24 h after ischemia. Although minocycline diminished leukocyte accumulation in the kidney following ischemia, areas of leukocyte accumulation did not correlate with areas of microvascular permeability in either the saline- or minocycline-pretreated animals. Minocycline diminished the perivascular increase in MMP-2 and MMP-9, as well as the increase in MMP-2 activity 24 h after ischemia. ABT-518, a specific inhibitor of MMP-2 and MMP-9, also significantly reduced the extent of dextran (500 kDa) leakage from the renal microvasculature 24 h after ischemia. Our results indicate that minocycline mitigates the renal microvascular permeability defect following IRI. This effect is spatially distinct from the effect of minocycline on leukocyte accumulation and may be related to diminished activity of MMPs on the integrity of the perivascular matrix.
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PMID:Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury. 1535 1

Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-D-aspartate (NMDA) NR1 subunit, amplification of intracellular Ca++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.
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PMID:The neurotoxicity of tissue plasminogen activator? 1535 16

Abnormal expression and activity of matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral disease such as ischemic injury. In this study, we compared the cellular localization, expression, and activity of MMP-2 and -9 in relation to the evolution of neuronal damage 24 and 72 h after transient global ischemia. In response to ischemia, there was a generalized increase in cellular MMP-2 immunoreactivity at 24-h reperfusion (in neurons, glia and vessels) whereas at 72-h reperfusion the increase in MMP-2 was predominantly in glia. These glial alterations contributed to a significant increase in pro MMP-2 levels in ischemic regions (P < 0.01) as measured by zymography. In contrast, MMP-9 was predominantly upregulated in neurons and this was significantly different to shams at 24- and 72-h reperfusion after ischemia (P < 0.05). Notably, a dramatic increase in proteolytic activity in neurons was observed 24 h after ischemia and this response was absent at 72 h post-ischemia. The present data are supportive of a role for MMPs in contributing to neuronal injury after ischemia.
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PMID:Differential alterations in the expression and activity of matrix metalloproteinases 2 and 9 after transient cerebral ischemia in mice. 1547 57

Angiostatin, an inhibitor of tumor angiogenesis, is produced by the actions of matrix metalloproteinases (MMP) on plasminogen. Recently, we reported that angiostatin levels are increased in a model of inadequate coronary collateral growth and angiogenesis in response to ischemia, despite high levels of vascular endothelial growth factor (VEGF). We hypothesized that angiostatin levels are negatively associated with collateral formation in patients. Coronary angiograms from 37 patients undergoing coronary bypass surgery were evaluated for the absence of angiographically visible collaterals (Rentrop scores of 0) or the presence of Rentrop classification grade 3 (well developed) collaterals. Pericardial fluid was obtained from each patient during the bypass procedure, and the sample was analyzed for angiostatin, plasminogen, and VEGF (Western analysis) and for combined activities of MMP-2 and MMP-9 (zymographic analysis). In patients with no collaterals, angiostatin level was greater compared with that in patients with well-developed collaterals (3.1 +/- 0.2 vs. 2.3 +/- 0.1 optical density units, P < 0.05). Neither MMP activities nor VEGF levels were different between the two groups of patients. The higher levels of angiostatin in patients with no visible collaterals were reflective of a higher concentration of plasmin/plasminogen (6.2 +/- 0.7 vs. 4.2 +/- 0.5 optical density units, P < 0.05) compared with those in patients with well-developed collateral vessels. Our results support the concept that the growth inhibitor angiostatin may have a negative impact on coronary collateral growth in patients. Perhaps therapies attempting to provoke coronary collateral growth should incorporate approaches to limit or neutralize the effects of growth inhibitors.
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PMID:Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. 1584 Sep 2

Although ischemia remains the leading cause of acute renal failure in humans, there is little information on the expression and activities of gelatinases of kidney glomeruli during ischemia-reperfusion injury. In this study, we used a unilateral ischemia-reperfusion model to investigate the activity and expression of gelatinases in glomeruli during acute ischemia. Unilateral ischemia was induced in rats by vascular clamping (30 min) followed by reperfusion (60 min) and isolation of glomeruli. The activity and expression of gelatinase proteins were determined by gelatin zymography and Western blotting. Gelatinase mRNA levels were evaluated by reverse transcriptase-PCR. Ischemia and reperfusion increased serum creatinine levels, hallmark of acute renal failure. Ischemia induced mRNA and protein MMP-2 expression. There was strong stimulation of MMP-9 mRNA, both forms of dimeric MMP-9, and active monomeric MMP-9. In contrast to TIMP-1 decreasing, TIMP-2 protein and mRNA increased during ischemia. During reperfusion, there was a gradual reversal of the MMP-2 and MMP-9 levels and a strong inhibition of TIMP-1 and TIMP-2 at the protein and mRNA levels. Endocytic receptor LRP was increased during ischemia and returned to normal during reperfusion. Expression of MMP-9 docking receptor CD-44 was increased during reperfusion. Finally, ZO-1, an in vivo MMP-9 substrate, was degraded during ischemia, revealing that MMP-9 upregulated during ischemia was functional. Our data suggest that stimulation of gelatinase activity during ischemia could contribute to glomeruli injury, providing new therapeutic targets for acute renal failure in humans. In contrast, elevated monomeric MMP-9 activity due to TIMP-1 decrease during reperfusion may participate to glomerular recovery.
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PMID:Ischemia-reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. 1587 Aug 43


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