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)

Several lines of evidence show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a component of endothelial cell junctions, is required for leukocyte transmigration through endothelial cell monolayers. Polymorphonuclear leukocytes play an important role in ischemia-reperfusion injury. We sought to determine whether administering an anti-PECAM-1 antibody would prevent or attenuate ischemia-reperfusion injury in a rat cremaster muscle flap injury model. Eighteen male Sprague-Dawley rats were divided into three groups. Group I (control): Cremaster muscle island flaps were dissected for baseline measurements of eight indicators: numbers of rolling, sticking, and transmigrating neutrophils, numbers of rolling and sticking lymphocytes, number of perfused capillaries, endothelial edema, and vessel permeability. Group II: The prepared cremaster flap was subjected to 4 hours of ischemia and 24 hours of reperfusion. Group III: The muscle flap was subjected to ischemia and reperfusion as in group II, and anti-PECAM-1 antibodies (1 mg/kg) were injected subcutaneously 15 minutes before reperfusion. Blood vessels were observed in vivo under an intravital microscopy system. Microvascular permeability was made visible with injected fluorescein isothiocyanate-labeled albumin and evaluated with Kontron Elektronik computer software. The ischemia-reperfusion-alone group (group II) presented a 225-percent increase in the activation of sticking leukocytes (2.4 +/- 0.4 to 7.8 +/- 0.8, p < 0.05) (p < 0.01). This leukocyte activation was reduced by 83 percent following anti-PECAM-1 monoclonal antibody treatment (1.3 +/- 0.5 per 100 microm) (p < 0.01). At 24 hours, endothelial injury in group II was confirmed by a 4-fold increase in the number of transmigrating leukocytes into the interstitial space (7.6 +/- 1.2 per field versus 1.9 +/- 0.4 per field in controls). This phenomenon was reduced by 85 percent following anti-PECAM-1 monoclonal antibody treatment (1.1 +/- 0.2 per field) (p < 0.01). Analysis showed that the number of flowing capillaries was 67 percent lower in group II (6.8 +/- 0.3 to 2.2 +/- 0.7, p < 0.01). Anti-PECAM-1 antibody treatment caused a 2.5-fold increase in this number (5.6 +/- 0.5, p < 0.01). Microcirculatory permeability index showed a 180-percent increase in group II (p < 0.05) when compared with baseline values. This increased albumin leakage was effectively attenuated by antibody treatment (p < 0.05). Blocking the action of PECAM-1 in vivo by administering monoclonal antibodies significantly attenuated ischemia-reperfusion injury, presumably by inhibiting transendothelial migration of neutrophils and by increasing capillary perfusion at a muscle flap microcirculatory level.
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PMID:Blockade of platelet endothelial cell adhesion molecule-1 (PECAM-1) protects against ischemia-reperfusion injury in muscle flaps at microcirculatory level. 1065 44

Calpains are ubiquitous Ca(2+)-activated neutral proteases that have been implicated in ischemic and traumatic CNS injury. Ischemia and trauma of central white matter are dependent on Ca2+ accumulation, and calpain overactivation likely plays a significant role in the pathogenesis. Adult rat optic nerves, representative central white matter tracts, were studied in an in vitro anoxic model. Functional recovery following 60 min of anoxia and reoxygenation was measured electrophysiologically. Calpain activation was assessed using western blots with antibodies against calpain-cleaved spectrin breakdown products. Sixty minutes of in vitro anoxia increased the amount of spectrin breakdown approximately 20-fold over control, with a further increase after reoxygenation to >70 times control, almost as much as 2 h of continuous anoxia. Blocking voltage-gated Na+ channels with tetrodotoxin or removing bath Ca2+ was highly neuroprotective electrophysiologically and resulted in a marked reduction of spectrin degradation. The membrane-permeable calpain inhibitors MDL 28,170 and calpain inhibitor-I (10-100 microM) were effective at reducing spectrin breakdown in anoxic and reoxygenated optic nerves, but no electrophysiological improvement was observed. We conclude that calpain activation is an important step in anoxic white matter injury, but inhibition of this Ca(2+)-dependent process in isolation does not improve functional outcome, probably because other deleterious Ca(2+)-activated pathways proceed unchecked.
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PMID:Calpain inhibitors confer biochemical, but not electrophysiological, protection against anoxia in rat optic nerves. 1080 Sep 55

Cation channels conduct calcium, sodium and potassium, cations that are likely deleterious in the evolution of focal ischemic injury. We studied the effects of a novel, broad-spectrum inhibitor of several cation channels, LOE 908 MS, on acute ischemic lesion development with diffusion-weighted magnetic resonance imaging (DWI) and on cerebral perfusion with perfusion imaging (PI) in vivo and on cerebral infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem. A total of 18 male Sprague-Dawley rats underwent 90 min of middle cerebral artery occlusion (MCAO) and were randomly and blindly assigned to either LOE 908 MS or vehicle starting 30 min after inducing focal ischemia and continuing for 4 h. Whole-brain DWI and multislice PI were done before initiation of treatment and repeated frequently for the next 3.5 h. DWI-derived lesion volume at 4 h showed a significant difference in favor of the drug treated group (P=0.03), whereas PI-derived perfusion deficit volumes did not significantly differ between the groups. The postmortem infarct volume at 24 h was significantly attenuated in the treated group in comparison to controls (P=0.0001) and neurological score was significantly better in the treated group (P<0.02). Blocking several distinct cation channels with LOE 908 MS significantly reduced infarct size and improved neurological outcome without observable adverse effects in this focal ischemia model.
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PMID:Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat. 1101 2

Ischemia leads to profound endothelin- (ET) related constriction of hepatic microvessels, causing disturbances in blood and oxygen supply. The aim of the study was to modulate hepatic microvascular diameters by blocking ET receptors to find the optimal therapeutic vessel width for reduction of ischemia-reperfusion injury. In an in vivo model (84 female Wistar rats, 250-300 g) with portal decompression by means of a splenocaval shunt, normothermic hepatic ischemia was induced for 30 min by crossclamping of the hepatoduodenal ligament. The ET receptor antagonist (ERA) bosentan was administered before induction of ischemia in different dosages [0.1, 1.0 and 10.0 mg/kg body weight (BW) i.v. and 10 mg/kg BW intraportally (i.p.)]. The effect on microcirculation was assessed by in vivo microscopy and influence on hepatocellular function by measurement of aspartate aminotransferase (AST) levels. Sinusoidal diameters were reduced as a result of ischemia to 76.3 +/- 7.4% compared with values received from sham-operated animals. After application of 0.1 mg/kg of bosentan, sinusoids remained constricted (89.7 +/- 9.9%, AST 255.0 +/- 12.8 U/l). Blocking ET receptors with 1 mg/kg bosentan avoided sinusoidal constriction (99.0 +/- 8.8%, p < 0.05) and led to the most effective reduction of AST level peak after 6 h of reperfusion (244.0 +/- 34.2 U/l vs 422.9 +/- 163.3 U/l in untreated ischemia). Bosentan (10 mg/kg i.v.) caused an increase in sinusoidal diameter to 109.1 +/- 6.4% (AST 311.7 +/- 33.6 U/l) and 10 mg/kg i.p. to 136.8 +/- 19.3% and even increase AST levels (618.90 +/- 209.32 U/l). After intravenous application of 1 and 10 mg/kg BW bosentan the perfusion rate was significantly increased and sticking of leukocytes in sinusoids and venules reduced (p < 0.05). In our model, diameters of sinusoids and postsinusoidal venules could be regulated gradually. We conclude that the avoidance of constriction, but not an excessive vasodilation leads to increased perfusion rate and hence improved hepatocellular function.
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PMID:Endothelin receptor blockade as a therapeutic strategy in ameliorating postischemic damage to the liver microcirculation. 1107 18

Adenosine (ADO) is a well-known regulator of a variety of physiological functions in the heart. In stress conditions, like hypoxia or ischemia, the concentration of adenosine in the extracellular fluid rises dramatically, mainly through the breakdown of ATP. The degradation of adenosine in the ischemic myocytes induced damage in these cells, but it may simultaneously exert protective effects in the heart by activation of the adenosine receptors. The contribution of ADO to stimulation of protective effects was reported in human and animal hearts, but not in rat hearts. The aim of this study was to evaluate the role of adenosine A1 and A3 receptors (A1R and A3R), in protection of isolated cardiac myocytes of newborn rats from ischemic injury. The hypoxic conditions were simulated by exposure of cultured rat cardiomyocytes (4-5 days in vitro), to an atmosphere of a N2 (95%) and CO2 (5%) mixture, in glucose-free medium for 90 min. The cardiotoxic and cardioprotective effects of ADO ligands were measured by the release of lactate dehydrogenase (LDH) into the medium. Morphological investigation includes immunohistochemistry, image analysis of living and fixed cells and electron microscopy were executed. Pretreatment with the adenosine deaminase considerably increased the hypoxic damage in the cardiomyocytes indicating the importance of extracellular adenosine. Blocking adenosine receptors with selective A1 and A3 receptor antagonists abolished the protective effects of adenosine. A1R and A3R activation during the hypoxic insult delays onset of irreversible cell injury and collapse of mitochondrial membrane potential as assessed using DASPMI fluorochrom. Cardioprotection induced by the A1R agonist, CCPA, was abolished by an A1R antagonist, DPCPX, and was not affected by an A3R antagonist, MRS 1523. Cardioprotection caused by the A3R agonist, Cl-IB-MECA, was antagonized completely by MRS 1523 and only partially by DPCPX. Activation of both A1R and A3R together was more efficient in protection against hypoxia than by each one alone. Our study indicates that activation of either A1 or A3 adenosine receptors in the rat can attenuate myocyte injury during hypoxia. Highly selective A1R and A3R agonists may have potential as cardioprotective agents against ischemia or heart surgery.
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PMID:Cardioprotective effects of adenosine A1 and A3 receptor activation during hypoxia in isolated rat cardiac myocytes. 1126 59

The RING (really interesting new gene) finger proteins containing a characteristic C3HC4 or C3H2C3 motif appear to act as E3 ubiquitin ligase and play important roles in many processes, including cell-cycle progression, oncogenesis, signal transduction, and development. This review is focused on SAG/ROC/Rbx/Hrt (sensitive to apoptosis gene/regulator of cullins/RING box protein), an evolutionarily conserved RING finger family of proteins that were cloned recently by several independent laboratories through differential display, yeast two-hybrid screening, or biochemical purification. SAG/ROC2/Rbx2/Hrt2 is expressed in multiple mouse adult tissues, as well as early embryos. In humans, both SAG and ROC1 are ubiquitously expressed at a very high level in heart, skeletal muscle, and testis. Expression of both SAG and ROC1 is induced by mitogenic stimulation. SAG is also induced by a redox agent in cultured cells, as well as in in vivo mouse brain upon ischemia/reperfusion. Structurally, SAG consists of four exons and three introns with at least one splicing variant and two pseudogenes. The SAG gene promoter is enriched with multiple transcription factor binding sites. Biochemically, SAG binds to RNA, has metal-ion binding/free radical scavenging activity, and is redox-sensitive. Most importantly, like ROC1, SAG/ROC2 binds to cullins and acts as an essential component of E3 ubiquitin ligase. Biologically, SAG is a growth-essential gene in yeast. In mammalian cells, SAG protects apoptosis mainly through inhibition of cytochrome c release/caspase activation, and promotes growth under serum deprivation at least in part by inhibiting p27 accumulation. Blocking SAG expression via antisense transfection inhibits tumor cell growth. Thus, SAG appears to be a valid drug target for anticancer therapy.
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PMID:SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. 1155 50

During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of nutrients and successively to radical oxygen species (ROS). In the present study, we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in their standard culture medium to simulate reperfusion. We investigated the effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP kinases activation to address the role of each event with respect to apoptosis. We demonstrate that serum/glucose depletion per se did not induce apoptosis when compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways. SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest that p38MAPK activation primarily mediates ROS-induced apoptosis while concomitant JNK activation would represent a scavenger pathway for cells trying to escape apoptosis.
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PMID:Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model. 1259 6

Cold cardioplegia protects against reperfusion damage. Blocking Na+/H+ exchange may be as protective as cardioplegia by improving the left ventricular pressure (LVP)-[Ca2+] relationship after cold ischemia. In guinea pig isolated hearts subjected to cold ischemia (4 h, 17 degrees C) and reperfusion, the cardioprotective effects of a Krebs-Ringer (KR) solution, a cardioplegia solution, a KR solution containing the Na+/H+ exchange inhibitor eniporide (1 microM), and a cardioplegia solution containing eniporide were compared. Treatments were given before and initially after cold ischemia. Systolic and diastolic [Ca2+] were calculated from indo-1 fluorescence transients recorded at the LV free wall. During ischemia, diastolic [Ca2+] increased in each group but more so in the KR group. Peak systolic and diastolic [Ca2+] on initial reperfusion were highest after KR and smallest after cardioplegia + eniporide. After reperfusion, systolic-diastolic LVP (% of baseline) and infarct size (%), respectively, were KR, 47 +/- 3%, 37 +/- 4%; cardioplegia, 71 +/- 5%*, 20 +/- 2.2%*; KR + eniporide, 73 +/- 5%*, 11 +/- 3%* dagger; and cardioplegia + eniporide 77 +/- 3%*, 10 +/- 1.4%* dagger (*P </= 0.05 vs KR; dagger P </= 0.05 vs cardioplegia). Ca2+ overload was reduced in each treated group, and most in the cardioplegia + eniporide group, and was associated with the improved function. Inhibition of Na+/H+ exchange was as effective as cardioplegia in restoring function and better than cardioplegia in reducing infarct size after hypothermic ischemia. The combination of cardioplegia and Na+/H+ exchange inhibition did not produce additive protective effects but caused a larger decrease in Ca2+ loading.
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PMID:Na+/H+ exchange inhibition with cardioplegia reduces cytosolic [Ca2+] and myocardial damage after cold ischemia. 1271 98

Oxidative stress or signaling is widely implicated in apoptosis, ischemia and mitogenesis. Previously, our group reported that the hydrogen peroxide (H2O2)-dependent activation of phospholipase D2 (PLD2) in PC12 cells is involved in anti-apoptotic effect. However, the precise mechanism of PLD2 activation by H2O2 was not revealed. To find H2O2-dependent PLD2-regulating proteins, we immunoprecipitated PLD2 from PC12 cells and found that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) coimmunoprecipitated with PLD2 upon H2O2 treatment. This interaction was found to be direct by in vitro reconstitution of purified GAPDH and PLD2. In vitro studies also indicated that PLD2-associated GAPDH was modified on its reactive cysteine residues. Koningic acid, an alkylator of GAPDH on catalytic cysteine residue, also increased interaction between the two proteins in vitro and enhanced PLD2 activity in PC12 cells. Blocking H2O2-dependent modification of GAPDH with 3-aminobenzamide resulted in the inhibition of the GAPDH/PLD2 interaction and attenuated H2O2-induced PLD2 activation in PC12 cells. From the results, we suggest that H2O2 modifies GAPDH on its catalytic cysteine residue not only to inactivate the dehydrogenase activity of GAPDH but also to endow GAPDH with the ability to bind PLD2 and the resulting association is involved in the regulation of PLD2 activity by H2O2.
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PMID:Hydrogen peroxide induces association between glyceraldehyde 3-phosphate dehydrogenase and phospholipase D2 to facilitate phospholipase D2 activation in PC12 cells. 1275 82

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
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PMID:Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. 1283 3


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