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)

Oxidative stress generated during stroke is a critical event leading to blood-brain barrier (BBB) disruption with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of thrombolytic reperfusion. In this study, the authors demonstrate that ischemia-reperfusion-induced BBB disruption in mice deficient in copper/zinc-superoxide dismutase (SOD1) was reduced by 88% ( P < 0.0001) and 73% ( P < 0.01), respectively, after 3 and 7 hours of reperfusion occurring after 1 hour of ischemia by the inhibition of matrix metalloproteinases. Accordingly, the authors show that local metalloproteinase-generated proteolytic imbalance is more intense in ischemic regions of SOD1 mice than in wild-type litter mates. Moreover, active in situ proteolysis is, for the first time, demonstrated in ischemic leaking capillaries that produce reactive oxygen species. By showing that oxidative stress mediates BBB disruption through metalloproteinase activation in experimental ischemic stroke, this study provides a new target for future therapeutic strategies to prevent BBB disruption and potentially reperfusion-triggered intracerebral hemorrhage.
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PMID:Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. 1174 Feb

Activated protein C (APC) is useful in the treatment of sepsis. Ischemia and acidosis, which often accompany sepsis, cause the release of copper from loosely bound sites. We investigated (i) whether physiological concentrations of copper inhibit APC anticoagulant activity and (ii) if any copper-induced APC inhibition is reversible by human serum albumin (HSA) or a high-affinity copper-binding analogue of the human albumin N-terminus, d-Asp-d-Ala-d-His-d-Lys (d-DAHK). APC activity after 30 min of incubation with CuCl2 (10 microM) was decreased 26% below baseline. HSA, both alone and when combined with various ratios of CuCl2, increased APC activity significantly above baseline. d-DAHK alone and 2:1 and 4:1 ratios of d-DAHK:CuCl2 also increased APC activity. APC contained 1.4 microM copper, which helps explain the increased APC activity with HSA and d-DAHK alone. These in vitro results indicate that copper inhibits APC activity and that albumin and d-DAHK reverse the copper-induced APC deactivation.
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PMID:Copper inhibits activated protein C: protective effect of human albumin and an analogue of its high-affinity copper-binding site, d-DAHK. 1182 Jul 75

The N-terminus region of human albumin binds strongly to trace metals (Co, Cu, Ni). Ischemia, acidosis and reperfusion can cause a marked increase in plasma free Cu and its normal regulation by plasma proteins may be overwhelmed and predispose to oxidative injury by Cu-catalyzed oxyradical production. H4DUS60131 is an analogue of the N-terminus of human albumin, it binds copper tightly and in vitro, is a potent inhibitor of Cu-catalyzed radical formation. We have tested the ability of H4DUS60131 to reduce injury during ischemia and reperfusion in isolated blood-perfused rat hearts (n = 6/group) subjected to 20-min aerobic perfusion, followed by a 2-min infusion of saline or saline plus H4DUS60131. Following infusion, hearts were subjected to 30-min global ischemia plus 40-min reperfusion. The 2-min infusion was repeated in both groups at the start of reperfusion. In the vehicle controls, left ventricular developed pressure recovered to only 15.3 +/- 3.2%, whereas the H4DUS60131 group recovered to 50.5 +/- 9.3% (p < 0.005). The H4DUS60131 group normalised their left ventricular end diastolic pressure more quickly and completely than the controls (44.1 +/- 11.5 vs. 91.5 +/- 5.5 mm Hg). In conclusion, H4DUS60131 greatly improves the recovery of the rat heart from ischemia and reperfusion and may represent a novel approach to the limitation of myocardial injury.
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PMID:Attenuation of trace element-mediated injury during ischemia and reperfusion by an N-terminus analogue of human albumin (H4DUS60131). 1197 16

Transition metals such as iron and copper potentiate the postischemic reperfusion (I/R) injury induced by oxygen-derived radical and nonradical toxic species (ROS). Various natural and synthetic antioxidants have been previously tested to ameliorate such injury, yet the limitations of the common antioxidants are well known. An alternative strategy for combating oxidative damage is presented wherein cell-permeable, nitroxide stable radicals, which act as SOD-mimics and oxidize reduced metals thus prompting the Fenton-like chemistry, are investigated for utility in ameliorating I/R injury. Our study concentrates on the early effect of nitroxide on the myocardial I/R injury. Isolated rat hearts in the Langendorff configuration were equilibrated with Krebs-Henseleit buffer and then subjected to 18 min of normothermic global ischemia followed by 20 min reperfusion. Iron administered as Fe(III)-citrate (10 microM) did not affect the cardiac function under normoxia but did potentiate I/R injury and decreased the recovery during reperfusion. The iron-induced damage was manifested by further deterioration of the cardiac hemodynamic function and the energy status as reflected by decreased tissue level of phosphorylated nucleotides. Nitroxide at 200 microM protected against the iron-potentiated I/R injury by improving the recovery of the hemodynamic function and the cardiac energy status. Exogenously added iron requires bioreduction to form deleterious Fe(II) bound to critical cellular sites. The nitroxide, which enters the cell and oxidizes the reduced metal instantaneously, provided protection even when administered 2 or 3.5, but not 5 min, after the onset of reperfusion. Thus, its narrow therapeutic time window provides insight into the schedule of the I/R injurious process.
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PMID:Time window of nitroxide effect on myocardial ischemic-reperfusion injury potentiated by iron. 1197 93

Vascular endothelial cells are the prime target in ischemia reperfusion injury. Growing evidence has shown that one of the main etiologies is considered to be reactive oxygen species (ROS) that induce endothelial-cell death either by necrosis or apoptosis. Cultured porcine endothelial cells were transfected with human copper, zinc-superoxide dismutase (h-Cu, Zn-SOD) to investigate whether these cells can prevent apoptosis from oxidative injury in vitro. The endothelial cells were cultured with SIN-1 (3-morpholinosydnonimine-N-ethylcarbanride) as a donor of peroxinitrite (ONOO(-)). The control cells without the gene transfection developed characteristic apoptotic changes both morphologically and biochemically when they were incubated with SIN-1 of 200 M. However, the cells showed necrosis predominantly when the concentration of SIN-1 was 1,000 M. On the other hand, the cells transfected with h-Cu, Zn-SOD showed significantly less evidence of apoptotic change after exposure to SIN-1. Nitric oxide (NO) did not significantly affect the viability of either the control cells or the transfected cells. One of the potent ROS, peroxinitrite, is considered to play a significant role in ischemia reperfusion injury. SIN-1 can produce peroxinitrite in vitro that induces endothelial-cell damage by apoptosis. This type of cytotoxicity can be successfully prevented by transfection of the h-Cu, Zn-SOD into the cells.
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PMID:Prevention of free-radical induced apoptosis by induction of human recombinant Cu, Zn-SOD in pig endothelial cells. 1201 42

Hemodynamic disorders in brain dead organ donors induce hypoxia, warm ischemia and finally tissue damage. A cold preservation period also induces tissue and cellular lesions. The two major modes of preservation are cold storage (CS) and hypothermic pulsatile perfusion (HPP). We aimed to compare the influence of each mode of preservation and their combination on oxidative stress, perfusion characteristics and tissue damage, after a period of warm ischemia. Rat kidneys which had undergone ischemia (0, 30, 60 min) were preserved either by CS (12, 24 h), or by HPP (12 h), or by a combination of both (HPP+CS, CS+HPP), in University of Wisconsin cold storage solution (UWCSS) at + 4 degrees C. During HPP, renal vascular pressure decreased then increased to reach 90 mmHg after perfusion for 7 h. If HPP followed CS, the mean pressure reached 200 mmHg, showing successive high amplitude peaks. HPP had a deleterious effects on tissue structure with tubular necrosis, and induced an increase in catalase (Cat) and a decrease in manganese superoxide dismutase (Mn SOD) and gluthatione peroxidase (GPx) activity. Copper zinc superoxide dismutase (Cu/Zn SOD) activity was not reduced except with CS+HPP. During CS, we observed an increase in GPx, Cu/Zn SOD and Cat activity, a decrease in Mn SOD activity and no histological alterations in the kidney. CS induces a slight oxidative stress which is not important enough to induce major tissue damage. HPP with UWCSS induces a stronger stress, which overpowers the antioxidant defences, inducing tissue damage. The reperfusion of HPP with UWCSS emphasises the stress initiated by CS. In addition an increase in damage occurred in the CS + HPP group.
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PMID:Impact of different combined preservation modalities on warm ischemic kidneys: effect on oxidative stress, hydrostatic perfusion characteristics and tissue damage. 1208 21

The intensity of free radical processes and the regulation of NADP-isocitrate dehydrogenase (EC 1.1.1.42; NADP-IDH) activity have been studied in the cytoplasmic fraction of normal and ischemized rat myocardium. Chemiluminescence parameters, such as the light sum (S) of slow flash and the tangent of the kinetic curve slope angle (tanalpha1), which characterize the intensity of free radical processes, were increased in ischemia 2.1- and 20.0-fold, respectively. The slow flash intensity (Imax) was increased 22-fold. The contents of lipid peroxidation products--diene conjugates and malonic dialdehyde--were increased 11.9- and 4.7-fold, respectively, suggesting pronounced oxidative stress. Using homogenous enzyme preparations of NADP-IDH isolated from the normal and experimentally ischemized rat myocardium, a number of catalytic properties of the enzyme were characterized for normal and pathologic conditions. NADP-IDH from the normal and ischemized myocardium had the same electrophoretic mobility and was regulated similarly by Fe2+, Cu2+, Zn2+, and also with succinate and fumarate. However, under normal and pathologic conditions NADP-IDH was different in the affinity for substrates and in the sensitivity to inhibitory effects of hydrogen peroxide, reduced glutathione, and of Ca2+. The degree of synergy in the enzyme inhibition with Fe2+ and H2O2 was less pronounced in ischemia. The inhibitory effect of the reaction product 2-oxoglutarate was higher under normal conditions than in ischemia (the Ki values were 0.22 and 0.75 mM, respectively). The specific features of the NADP-IDH regulation in ischemia are suggested to promote the stimulation of the enzyme functioning during increased level of free radical processes, and this seems to be important for NADPH supplying for the glutathione reductase/glutathione peroxidase antioxidant system of cardiomyocytes.
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PMID:Intensity of free radical processes and regulation of cytoplasmic NADP-isocitrate dehydrogenase in rat cardiomyocytes under normal and ischemic conditions. 1212 79

Iron and copper play major roles in biological systems, catalyzing free radical production and consequently causing damage. The relatively high levels of these metals, which are mobilized into the coronary flow following prolonged ischemia, have been incriminated as key players in reperfusion injury to the heart. In the present communication we investigated other roles of iron - providing protection to the ischemic heart via preconditioning (PC). PC was accomplished by subjecting isolated rat hearts to three episodes of 2 min ischemia separated by 3 min of reperfusion. Prolonged ischemia followed the PC phase. PC hearts (group I) were compared to hearts subjected to normal perfusion (group II, no ischemia) and to ischemia without PC (group III). Group I showed a marked improvement in the recovery of hemodynamic function vs. group III. Biochemical parameters further substantiated the PC protection provided to group I against prolonged ischemia. Correspondingly, group I presented markedly lower re-distribution and mobilization of iron and copper into the coronary flow, following prolonged ischemia, as evinced from the decrease in total levels, and in the 'free' fraction of iron and copper. During the PC phase no loss of cardiac function was observed. A small wave of re-distribution and mobilization of iron (typically less than 4-8% of the value of 35 min ischemia) was recorded. The cellular content of ferritin (Ft) measured in the heart was significantly higher in group I than in group III (0.90 and 0.54 microg/mg, respectively). Also, iron-saturation of Ft was significantly lower for PC hearts, compared to both groups II and III (0.22 vs. 0.32 and 0.31 microg/mg, for 35 min ischemia, respectively). These findings are in accord with the proposal that intracellular re-distribution and mobilization of small levels of iron, during PC, cause rapid accumulation of ferritin - the major iron-storage protein. It is proposed that iron play a dual role: (i) It serves as a signaling pathway for the accumulation of Ft following the PC phase. This iron is not involved in cardiac injury, but rather prepares the heart against future high levels of 'free' iron, thus reducing the degree of myocardial damage after prolonged ischemia. (ii) High levels of iron (and copper) are mobilized following prolonged ischemia and cause tissue damage.
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PMID:Roles of ferritin and iron in ischemic preconditioning of the heart. 1216 45

INTRODUCTION: Heart transplantation is often accompanied by multiple functional alterations, especially in reperfusion period. These are probably related to the reactive oxygen species (ROS) formation catalyzed by transition metals such as iron and copper, and thus the preservation time of the donor hearts is limited. Metabolic protection of the heart grafts is a permanent objective of numerous experiments. Recently, an iron chelator deferoxamine (DFX) was proposed as antioxidant agent for storage solutions in heart grafts. Oxidative stress is also known to mediate the apoptotic cell death in different tissues during ischemia-reperfusion. METHODS: The aim of this study was to evaluate a possible role of DFX in prevention of apoptosis using in vitro model of isolated working rat heart and cold cardioplegia. Two groups of rats were evaluated: (a) group 'DFX 50 &mgr;M' (n=8) and (b) group 'controls' (n=8). Isolated rat hearts were perfused by Krebs-Henseleit buffer (KHB) for 30 min, arrested by cardioplegic solution and stored for 4 h in B21 solution at 4 degrees C. Then, the hearts were reperfused by KHB for 45 min. DFX was added to the cardioplegic and storage solutions and in KHB in reperfusion. Basic functional parameters were evaluated: coronary, aortic, cardiac outputs and heart rate. At the end of reperfusion period a tissue samples were taken from left ventricle and in situ detection of apoptotic cells was performed using an ApopTag kit. RESULTS: DFX significantly reduced the occurrence of apoptotic cells in myocardium (*P<0.05). Hearts treated by 50 &mgr;M of DFX showed also a better recovery of the cardiac output (***P<0.001). The presence of DFX in KHB, cardioplegic and storage solution reduced also the incidence of postischemic arrhythmias and fibrillation's but without statistical significance. CONCLUSIONS: Our results give evidence of the protective potential of DFX during cold ischemia and reperfusion, presumably due to its antioxidant properties. The significant decrease of apoptosis in hearts treated by DFX could be considered as an existence of close link between oxidative stress and apoptotic death promotion in ischemia-reperfusion injury.
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PMID:Prevention of apoptosis by deferoxamine during 4 hours of cold cardioplegia and reperfusion: in vitro study of isolated working rat heart model. 1238 62

BACKGROUND: Although several short-term animal models of stunning and hibernation have been studied extensively, it has been difficult to produce a consistent animal model of chronic hibernation. The aim of the present study was to develop a nonsurgical porcine stent model of coronary stenosis in order to investigate the relationship between chronic dysfunctional myocardium and viability using 2D-echo, dobutamine stress echo (DSE) and positron emission tomography (PET). METHODS AND RESULTS: Focal progressive coronary stenosis was induced by implantation of an oversized stent in the left anterior descending (LAD) and/or circumflex (LCX) coronary artery in a total of 115 pigs, according to various experimental protocols: copper stent in the LAD (group I, n = 5); noncoated stainless steel stent in the LAD combined with balloon overstretch (group II, n = 7); poly(organo)phosphazene-coated stent in the LAD (group III, n = 77); and poly(organo)phosphazene-coated stent in both the LAD and the LCX (group IV, n = 26). Occurrence of left ventricular dysfunction was evaluated weekly by 2D-echo. At the time of left ventricular dysfunction the presence of viable myocardium within the dysfunctional region was investigated with DSE and PET, and confirmed by histology. The degree of coronary artery stenosis was measured by quantitative coronary angiography and morphometry. Severe coronary artery stenosis in the presence of dysfunctional, but viable, myocardium was induced in groups III and IV (47% and 11% of the animals, respectively). CONCLUSIONS: The authors developed a nonsurgical porcine stent model of progressive coronary stenosis using an oversized polymer-coated stent resulting in chronically decreased myocardial function, with residual inotropic reserve and viable myocardium. This condition may arise from repetitive periods of ischemia, or from sustained hypoperfusion, or a combination of these processes eventually leading to myocardial hibernation.
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PMID:A nonsurgical porcine model of left ventricular dysfunction. Validation of myocardial viability using dobutamine stress echocardiography and positron emission tomography. 1247 Mar 78


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