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)

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

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

Reactive oxygen species play a critical role in ischemic injury and oxidative stress induces apoptosis and triggers inflammation in neural cells. The effect of ethanol on ischemic brain injury was examined. Ethanol attenuated ischemia/reperfusion-induced brain infarction and elevation of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha) expression, metalloproteinase-9, and neutrophil-associated myeloperoxidase activities. In cultured neurons, ethanol suppressed combined oxygen and glucose deprivation (COGD)/reoxygenation-induced oxidative stress and neuronal apoptosis. Furthermore, ethanol suppressed COGD/reoxygenation-induced activation of NF-kappaB, a free-radical-sensitive regulator, leading to the attenuation of TNF-alpha expression in glial cultures. We propose that scavenging of free radicals and attenuation of free-radical-induced alterations might account for ethanol's beneficial action against ischemic brain injury.
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PMID:Ethanol attenuates ischemic and hypoxic injury in rat brain and cultured neurons. 1460 May 3

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

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

Hibernation is a potential protective strategy for the peripheral, as well as for the central nervous system. A protein factor termed hibernation induction trigger (HIT) was found to induce hibernation in summer-active ground squirrels. Purification of HIT yielded an 88-kD peptide that is enriched in winter hibernators. Partial sequence of the 88-kD protein indicates that it may be related to the inhibitor of metalloproteinase. Using opioid receptor antagonists to elucidate the mechanisms of HIT, it was found that HIT targeted the delta opioid receptors. Indeed, delta opioid (D-Ala 2, D-Leu 5) enkephalin (DADLE) was shown to induce hibernation. Specifically, HIT and DADLE were found to prolong survival of peripheral organs, such as the lung, the heart, liver, and kidney preserved en bloc or as a single preparation. In addition, DADLE has been recently demonstrated to promote survival of neurons in the central nervous system. Exposure to DADLE dose-dependently enhanced cell viability of cultured primary rat fetal dopaminergic cells. Subsequent transplantation of these DADLE-treated dopaminergic cells into the Parkinsonian rat brain resulted in a two-fold increase in surviving grafted cells. Interestingly, delivery of DADLE alone protected against dopaminergic depletion in a rodent model of Parkinson s disease. Similarly, DADLE blocked and reversed the dopaminergic terminal damage induced by methamphetamine (METH). Such neuroprotective effects of DADLE against METH neurotoxicity was accompanied by attenuation of mRNA expressions of a tumor necrosis factor p53 and an immediate early gene c-fos. In parallel to these beneficial effects of DADLE on the dopaminergic system, DADLE also ameliorated the neuronal damage induced by ischemia-reperfusion following a transient middle cerebral artery occlusion. In vitro replication of this ischemia cell death by serum-deprivation of PC12 cells revealed that DADLE exerted neuroprotection in a naltrexone-sensitive manner. These results taken together suggest that DADLE stands as a novel therapeutic agent. In this review paper, we present laboratory evidence supporting the use of DADLE for protection of peripheral and central nervous system.
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PMID:Delta opioid peptide (D-Ala 2, D-Leu 5) enkephalin: linking hibernation and neuroprotection. 1535 66

Neuregulin (NRG)-1beta has a prosurvival effect on cardiac myocytes via the phosphatidylinositol-3-kinase/Akt pathway, but the physiological regulators of this system in the intact heart are unknown. In this study, we tested the hypothesis that reactive oxygen species regulate NRG/erbB signaling. We used isolated adult rat ventricular myocytes (ARVMs) or cardiac microvascular endothelial cells (CMECs) in monoculture, or together in coculture. H2O2 induced NRG-1beta release from CMECs in a concentration-dependent manner, and conditioned medium from H2O2-treated CMEC activated ARVM erbB4. NRG-1beta release occurred via proteolytic cleavage of 115-kDa transmembrane NRG-1beta and was inhibited by the metalloproteinase inhibitor 1,10-phenanthroline. In myocyte monoculture, H2O2 induced erbB4-dependent, but NRG-independent, activation of Akt. To elucidate the bioactivity of CMEC-derived NRG-1beta on ARVMs, we examined H2O2-induced myocyte apoptosis in co-culture using an antibody to NRG-1beta. The percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly higher in the anti-NRG-1beta group than in the control group. The change in apoptosis induced by anti-NRG-1beta in co-culture was similar in magnitude to the protection of myocytes by addition of recombinant NRG-1beta to ARVM monocultures. Activation of NRG/erbB paracrine signaling was also seen in the intact heart subjected to oxidative stress by ischemia-reperfusion injury. Isolated perfused mouse hearts subjected to 15 min of ischemia, followed by 30 min of reperfusion, showed complete proteolytic cleavage of 115-kDa NRG-1beta, with concomitant erbB4 phosphorylation. These results demonstrate that reactive oxygen species activate NRG-1beta/erbB4 paracrine signaling in the heart and suggest that this system is involved in cardiac adaptation to oxidative stress.
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PMID:Cardiac endothelial cells regulate reactive oxygen species-induced cardiomyocyte apoptosis through neuregulin-1beta/erbB4 signaling. 1538 48

Although ischemia has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia-reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of PBS solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited extracellular 80-kDa and intracellular 40-kDa E-cadherin fragments after 4 h of ischemia, and at 6 h the expression of full-length E-cadherin decreased. While no fragments of N-cadherin, alpha-catenin, and gamma-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 h of ischemia. The MMP inhibitors GM-6001 and TAPI-O inhibited cleavage and/or loss of E- and N-cadherin protein expression. Tissue inhibitors of metalloproteinases (TIMP)-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibit ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that are associated with a disruption of junctional contacts.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases. 1576 36

Extracellular matrix (ECM) metabolism and homeostasis is sensitive to changes in oxygen tension manifest in ischemia. We hypothesize that in chronically ischemic limbs, abnormalities in uninjured skin, secondary to hypoxia, predispose to dermal breakdown. Paired biopsies of uninjured distal ischemic and proximal non-ischemic skin were harvested at below knee amputation from 14 patients with peripheral vascular disease following quantification of ischemia. Age- and site-matched controls were taken at total knee replacement (TKR) and varicose vein (VV) operations. Matrix metalloproteinase (MMP)-2 and -9 expression was determined using gelatin zymography, MMP-1 by western blotting and ELISA and tissue inhibitor of MMP (TIMP) by reverse zymography. Collagen content was measured by determining hydroxyproline levels, and collagen type I synthesis by ELISA. Collagen type I synthesis was upregulated in ischemic tissue compared with non-ischemic matched pairs (p<0.001) and both TKR and VV controls, however, there was no increase in collagen deposition. Levels of MMP-2 (p<0.0005) and TIMP-2 (p<0.01), were elevated in ischemic samples. MMP-9 was unaltered, signifying no inflammatory changes. Tissue ischemia was linked to elevated ECM turnover, associated with matrix failure when compounded with problems of matrix stabilization, likely in ischemia. This represents a potential mechanism for ulcer formation.
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PMID:Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. 1609 24

A hemorrhagic metalloproteinase has been isolated from Bothrops alternatus venom from specimens that inhabit the north-east region of Argentina. The present study aimed at evaluating the proteolytic, hemorrhagic, edematogenic and myotoxic activities of the purified metalloproteinase, in order to consider its participation on the phatophysiology of the intoxication by Bothrops alternatus venom. The hemorrhagic metalloproteinase was isolated by a combination of DEAE-Cellulose chromatography and gel filtration on Sephadex G-75. The enzyme showed a molecular mass around 55k Da, it exhibited a hemorrhagic activity with a minimal hemorrhagic dose of 1.9 microg, almost two fold minor than the whole venom (3.6 microg). The enzyme showed a weak proteolytic activity on casein (18.72 U/mg enzyme), similar to the one exhibited by the whole venom (20 U/mg venom). Besides, the ability to degrade casein could be detected by SDS-PAGE; beta-casein was the fraction that showed the higher degradation, followed by alphas(1)-casein and kappa-casein degradation. The hemorrhagic metalloproteinase rapidly hydrolysed the A alpha-chain of fibrinogen, followed by B beta-chain degradation and leaving the gamma-chain unaffected. Proteolytic activities were inhibited by EDTA whereas they were not inhibited by benzamidine and PMSF. The metalloproteinase showed several polypeptides chains after autocatalytic processing, including a chain of 28k Da, it could be the processed disintegrin-like and cysteine-rich domains. The isolated enzyme exhibited myotoxic activity with high CK levels at 6h, due to local ischemia resulting of its hemorrhagic activity, and a significant edema-inducing effect (MED=1.3 microg), corroborated both results by the histological observations of samples of gastrocnemius muscle. These findings showed that this hemorrhagic metalloproteinase, possesses high edematogenic and myotoxic activities and, in despite of exhibiting a weak proteolytic activity, it is able to degrade fibrinogen. So, this enzyme would contribute markedly to the phatophysiology of the bothropic envenomation.
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PMID:Proteolytic, edematogenic and myotoxic activities of a hemorrhagic metalloproteinase isolated from Bothrops alternatus venom. 1613 35


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