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)

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

Hepatocyte growth factor (HGF) is a plasminogen-like protein with an alpha chain linked to a trypsin-like beta chain without peptidase activity. The interaction of HGF with c-met, a receptor tyrosine kinase expressed by many cells, is important in cell growth, migration, and formation of endothelial and epithelial tubes. Stimulation of c-met requires two-chain, disulfide-linked HGF. Portions of an alpha chain containing an N-terminal segment and four kringle domains (NK4) antagonize HGF activity. Until now, no physiological pathway for generating NK4 was known. Here we show that chymases, which are chymotryptic peptidases secreted by mast cells, hydrolyze HGF, thereby abolishing scatter factor activity while generating an NK4-like antagonist of HGF scatter factor activity. Thus, chymase interferes with HGF directly by destroying active protein and indirectly by generating an antagonist. The site of hydrolysis, Leu480, lies in the alpha chain on the N-terminal side of the cysteine linking the alpha and beta chains. This site appears to be specific for HGF because chymase does not hydrolyze other plasminogen-like proteins, such as macrophage-stimulating protein and plasminogen itself. Mast cell/neutrophil cathepsin G and neutrophil elastase generate similar fragments of HGF by cleaving near the chymase site. Mast cell and neutrophil peptidases are secreted during tissue injury, infection, ischemia, and allergic inflammation, where they may oppose HGF effects on epithelial repair. Thus, HGF possesses an "inactivation segment" that serves as an Achilles' heel attacked by inflammatory proteases. This work reveals a potential physiological pathway for inactivation of HGF and generation of NK4-like antagonists.
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PMID:Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. 1630 61

Plasminogen kringle 5 (K5), a proteolytic fragment of plasminogen, is an endogenous angiogenic inhibitor. We have previously shown that K5 inhibits ischemia-induced retinal neovascularization in a rat model. However, its anti-angiogenic potential and application in the treatment of neoplastic diseases have not been well investigated. Our present study was designed to test its effect on the neovascularization and growth of hepatocellular carcinoma, a typical hypervascular tumor. Recombinant human K5 was expressed in E. coli and purified by affinity chromatography. K5 inhibited proliferation and induced apoptosis of primary endothelial cells in dose-dependent manner, but no effect on pericytes from the same origin of endothelial cells, which suggested an endothelial cell-specific inhibition. Moreover, K5 had no effect on the proliferation and apoptosis of mouse HepA and human Bel7402 hepatoma cell lines even in the enhanced concentration range, which suggested K5 having no direct effect on tumor cells. Ventral injection of K5 significantly suppressed the tumor growth in graphed hepatocarcinoma mice model, which was established by injection of mouse HepA hepatoma cells. In xenografted hepatocarcinoma athymic mice model, which mimicked human tumors by injection of human Bel7402 hepatoma cells, K5 significantly suppressed the tumor growth. An average of 68% suppression of primary tumor growth was observed in the K5-treated mice compared with control group. K5 also inhibited intratumoral neovascularization in the two cancer models determined by micro vessel density (MVD) analysis. Injection of K5 significantly induced the cleavage of pro-caspase-3 in tumor tissues of grafted mouse model, which suggested K5 also induced apoptosis of tumor tissues and the decreased intratumoral microvascular density in K5 treated group may correlate with K5-induced endothelial cell apoptosis. These results suggest that tumor growth suppression of K5 depends on its anti-angiogenic activity and K5 could have therapeutic potential in hepatocellular carcinoma.
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PMID:Kringle 5 of human plasminogen suppresses hepatocellular carcinoma growth both in grafted and xenografted mice by anti-angiogenic activity. 1657 4

This is the case report of a 44-year-old woman presented with an acute stroke immediately after electroconvulsive therapy (ECT). The patient had no significant medical history other than chronic depression. She was taking sertraline, and she had had multiple previous ECT treatments without any complications. While being monitored in the recovery room within 10 minutes after the last ECT session, she was found to have sudden onset of left-sided flaccid hemiplegia and numbness along with slurred speech. On arrival to our hospital, she was found to have flaccid hemiplegia on the left side involving the face, arm, and leg (face and arm more than the leg involvement), severe dysarthria, and mild neglect syndrome (National Health Institute Stroke Scale of 14). Noncontrast computed tomography (CT) of the head showed no signs of early ischemia, and iodine contrast CT angiography revealed right middle cerebral artery (MCA) (distal M1 segment) clot. Patient received intravenous recombinant tissue plasminogen (rt-PA) at 2.5 hours after the onset of symptoms, and then a total of 3.0 mg of intra-arterial (IA) rt-PA. Angiography at the end of the procedure showed successful recanalization of the M1 segment and normal vessel caliber with adequate distal flow. After the procedure, the patient made rapid improvements in all of her initial symptoms during the first 24 hours. An extensive stroke workup failed to reveal any cause of the stroke, including usual stroke and hypercoagulable risk factors. This was an acute embolic stroke immediately following an ECT, and without the aggressive thrombolytic therapy, the patient's outcome would have been poor because there was an M1 segment clot with a major MCA syndrome with relatively high National Institute of Health Stroke Scale. The neurological side effect profile of ECT is reported to be minimal with most common symptoms being headache, disorientation, and memory complaints. There is no clear cause-and-effect relationship in this case, and the stroke after ECT is extremely rare. In such rare event of stroke while receiving ECT, there is an effective treatment available using both intravenous and IA thrombolysis as reported in this case.
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PMID:Acute embolic stroke after electroconvulsive therapy. 1663 11

Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system.
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PMID:Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia. 1716 29

The immature brains of newborns often respond differently from the brains of adults when exposed to similar insults. Previous studies have indicated that although hypoxia-ischemia (HI) induces persistent thrombosis in adult brains, it only modestly impairs blood perfusion in newborn brains. Here, we used the Vannucci model of HI encephalopathy to study age-related responses to cerebral HI in rat pups. We found that HI triggered fibrin deposition and impaired blood perfusion in both neonatal and adult brains. However, these effects were only transient in neonatal brains (<4 hours) and were accompanied by acute induction of both tissue-type and urinary-type plasminogen activators (tPA and uPA), which was not observed in adult brains subjected to the same insult. Interestingly, activation of the plasminogen system persisted up to 24 hours in neonatal brains, long after the clearance of fibrin-rich thrombi. Furthermore, astrocytes and macrophages outside blood vessels expressed tPA after HI, suggesting the possibility of tPA/plasmin-mediated cytotoxicity. Consistent with this hypothesis, injection of alpha2-antiplasmin into cerebral ventricles markedly ameliorated HI-induced damage to neurofilaments and white matter oligodendrocytes, providing a dose-response reduction of brain injury after 7 days of recovery. Conversely, ventricular injection of tPA increased HI-induced brain damage. Together, these results suggest that tPA/plasmin induction, which may contribute to acute fibrinolysis, is a critical component of extravascular proteolytic damage in immature brains, representing a new therapeutic target for the treatment of HI encephalopathy.
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PMID:Deleterious effects of plasminogen activators in neonatal cerebral hypoxia-ischemia. 1846 99

Clinical studies have shown that the treatment of ischemic stroke with hypothermia is promising. In this animal study, we investigated the fate of the microvasculature following focal cerebral ischemia in mice with and without hypothermia. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO) (3 h) with an intraluminal filament technique. Eight mice received normothermia (36.5 degrees C, NT) and eight received hypothermia (32-34 degrees C, HT) treatment during 24 h of reperfusion. Another six mice represented the sham group. Analysis of the hypothermic group in comparison to the normothermic group revealed a significantly reduced infarct volume (NT: 63.56+/-4.62 mm3 SEM, HT: 38.09+/-4.83 mm3 SEM; P<0.01) and showed considerably ameliorated neurological deficits (Garcia-score) after 24 h (P<0.01). In addition, the degradation of the microvascular basal lamina antigen collagen type IV after normothermia was strongly reduced (P<0.05) compared to sham. Hypothermia diminished this effect so that collagen type IV was not significantly reduced compared to sham. Moreover the hemoglobin extravasation was strongly reduced under hypothermic treatment compared to the normothermic group (P<0.01). In the hypothermia group the urokinase plasminogen-activator (uPA) activity (P=0.01) was significantly decreased compared to the normothermia group. Also MMP-9 was significantly reduced (P<0.05) during hypothermic treatment. In conclusion, for the first time we show in mice that hypothermia preserves the microvascular wall structures after ischemia. We have demonstrated that hypothermia protects the basal lamina, reduces the infarct volume and hemorrhage, and reduces proteolytic enzymes. These protective effects in an additional animal model of ischemia and reperfusion strongly recommend hypothermia as a potential beneficial treatment for stroke.
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PMID:Protection of cerebral microvasculature after moderate hypothermia following experimental focal cerebral ischemia in mice. 1858 14

Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
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PMID:Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. 1862 Nov 8

Catheter-directed thrombolysis is an important treatment option for many patients with acute lower extremity ischemia due to arterial and/or graft thrombosis. A growing body of evidence demonstrates that thrombolytic therapy for acute limb ischemia reduces the need for amputation; however, bleeding complications are more likely with lytic therapy. New direct-acting fibrinolytic compounds are being developed that facilitate thrombolysis while reducing the risk of bleeding. Plasmin, the active enzyme produced by all plasminogen activators, works directly upon thrombus and is neutralized instantly in the systemic circulation. This report reviews the principles for effective catheter directed thrombolysis for acute arterial occlusions and describes the development and evaluation of the new thrombolytic, plasmin.
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PMID:Development of catheter-directed intrathrombus thrombolysis with plasmin for the treatment of acute lower extremity arterial occlusion. 1870 Nov 42

TM601 is a synthetic polypeptide with sequence derived from the venom of the scorpion Leiurus quinquestriatus that has anti-neoplastic activity. It has recently been demonstrated to bind annexin A2 on cultured tumor and vascular endothelial cells and to suppress blood vessel growth on chick chorioallantoic membrane. In this study, we investigated the effects of TM601 in models of ocular neovascularization (NV). When administered by intraocular injection, intravenous injections, or periocular injections, TM601 significantly suppressed the development of choroidal NV at rupture sites in Bruch's membrane. Treatment of established choroidal NV with TM601 caused apoptosis of endothelial cells and regression of the NV. TM601 suppressed ischemia-induced and vascular endothelial growth factor-induced retinal NV and reduced excess vascular permeability induced by vascular endothelial growth factor. Immunostaining with an antibody directed against TM601 showed that after intraocular or periocular injection, TM601 selectively bound to choroidal or retinal NV and co-localized with annexin A2, which is undetectable in normal retinal and choroidal vessels, but is upregulated in endothelial cells participating in choroidal or retinal NV. Intraocular injection of plasminogen or tissue plasminogen activator, which like TM601 bind to annexin A2, also suppressed retinal NV. This study supports the hypothesis that annexin A2 is an important target for treatment of neovascular diseases and suggests that TM601, through its interaction with annexin A2, causes suppression and regression of ocular NV and reduces vascular leakage and thus may provide a new treatment for blinding diseases such as neovascular age-related macular degeneration and diabetic retinopathy.
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PMID:Agents that bind annexin A2 suppress ocular neovascularization. 2060 99


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