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)

We isolated and purified 35 kDa protein from the myocardium of the beagle dog and identified it to be annexin V from partial amino acid sequence determination. It was confirmed that anticanine cardiac annexin V rabbit polyclonal antibody, which was produced using the 35 kDa protein, cross-reacts with annexin V of the myocardium, lung, liver, kidney, and brain of the rat. The localization of cardiac annexin V and the effect of ischemia for 30-180 min in the rat were immunohistochemically studied with the use of the Langendorff perfusion heart. In the normal myocardium, annexin V, accompanied by cross-striation, was observed throughout the cell. In ischemia of 30 min, extracellular leakage of annexin V was observed with uneven staining in the cytoplasm. When the ischemic time exceeded 60 min, annexin V was observed in the cell membrane with a decrease of annexin V in the cytoplasm. Also, extracellular leakage of annexin V was observed prominently. In ischemia for 180 min, almost all the annexin V in the cytoplasm disappeared. These results suggest that the level of ischemia can be estimated from the changes in localization of annexin V.
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PMID:Purification of cardiac annexin V from the beagle dog heart and changes in its localization in the ischemic rat heart. 805 21

Dilated cardiomyopathy is a cardiac disease of unknown origin which is characterized by the gradual development of cardiac failure. Apoptosis, i.e. suicidal programmed cell death, may play a role in the development of heart failure. Only few studies have been carried out until now that describe the rate of apoptosis in human hearts with dilated cardiomyopathy. The numbers reported vary widely. This is also true for studies in different other cardiac diseases such as myocardial infarction or hibernating myocardium. The methods used to identify apoptosis include electron microscopy, labeling of the DNA fragments (TUNEL), staining with the Hoechst dye, annexin V labeling and documentation of DNA fragmentation using gel electrophoresis (laddering). None of these methods are totally reliable in tissue sections in which apoptosis is not a frequent event when they are not combined with another technique, e.g. TUNEL with electron microscopy or laddering. This has, however, only rarely been done. These technical difficulties may be the reason for the wide variation in the rate of apoptosis reported. From our own data we conclude that apoptosis plays a significant role in acute ischemia and in hibernating myocardium but its significance in the progression to heart failure in dilated cardiomyopathy has still to be established.
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PMID:The role of apoptosis in dilated cardiomyopathy. 1041 45

Oxidative stress may cause apoptosis of cardiomyocytes in ischemic-reperfused myocardium. We investigated whether ischemia-reperfusion modifies the susceptibility of cardiomyocyte induction of apoptosis by oxidative stress. Ischemia was simulated by incubating isolated cardiomyocytes from adult rats in an anoxic, glucose-free medium, pH 6.4, for 3 h. Annexin V-fluorescein isothiocyanate/propidium iodide staining and the detection of DNA laddering were used as apoptotic markers. H(2)O(2) (7.5 micromol/l) induced apoptosis in 20.1 +/- 1.8% of cells under normoxic conditions but only 14.4 +/- 1.6% (n = 6, P < 0.05) after ischemia-reoxygenation. This partial protection of ischemic-reoxygenated cells was observed despite a reduction in their cellular glutathione content, from 11.4 +/- 1.9 in normoxic controls to 2.9 +/- 0.8 nmol/mg protein (n = 3, P < 0.05). Elevation of end-ischemic glutathione contents by pretreatment with 1 mmol/l N-acetylcysteine entirely protected ischemic-reoxygenated cells against induction of apoptosis by H(2)O(2). In conclusion, ischemia-reperfusion can protect cardiomyocytes against induction of apoptosis by exogenous oxidative stress. This endogenous protective effect is most clearly demonstrated when control and postischemic cardiomyocytes are compared at similar glutathione levels.
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PMID:Influence of simulated ischemia on apoptosis induction by oxidative stress in adult cardiomyocytes of rats. 1064 88

Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2beta, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/44, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion.
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PMID:Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. 1072 88

The metabolic cocktail of glucose-insulin-potassium (GIK) has been shown to reduce mortality in humans and reduce infarct size in the rat when administered from the onset of reperfusion following an ischemic insult. The mechanisms underlying GIK mediated cardioprotection are, however, still unclear. Recent data implicates insulin "alone" as the major protagonist of cardioprotection when administered at the time of reperfusion. We have therefore begun to investigate an insulin activated signalling pathway and the putative role of apoptosis in this insulin-induced cardioprotection. Simulated ischemia and reoxygenation were induced in rat neonatal cardiocyte experiments. The administration of insulin [0.3 mU/ml] at the moment of reoxygenation (Ins(R)) enhanced myocardial cell viablility as assessed by trypan blue exclusion compared to vehicle alone treated control myocytes (Ins(R)50+/-2%v controls 70+/-1%, P<0.001). This insulin-mediated cardioprotection was due, in part to a reduction in myocyte apoptosis as measured by TUNEL (Ins(R)29+/-2%v controls 49+/-3%, P<0.001) and Annexin V staining (Ins(R)34+/-2%v controls 65+/-3%, P<0.001). These cardioprotective and anti-apoptotic effects of insulin were completely abolished by the tyrosine kinase inhibitor lavendustin A and by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin. Thus, we conclude that the early administration of insulin appears to be an effective modality to reduce reoxgygenation injury in cardiocytes, in part, via the attenuation of ischemia/reoxygenation-induced apoptosis. Moreover, the cardioprotective and anti-apoptotic effects of insulin are mediated via tyrosine kinase and PI3-kinase signalling pathways.
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PMID:Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. 1077 81

We assessed here the effect of the glucocorticoid-regulated protein lipocortin 1 (LC1) in a model of rat myocardial ischemia reperfusion. Treatment of animals with human recombinant LC1 at the end of a 25-min ischemic period significantly reduced the extent of infarct size in the area at risk as measured 2 h later, with approximately 50% inhibition at the highest dose tested of 50 microg per rat (equivalent to 5.4 nmol/kg). The protective effect of LC1 was abolished by protein denaturation and not mimicked by the structurally related protein annexin V. A combination of electron and light microscopy techniques demonstrated the occurrence of the myocardial damage at the end of the reperfusion period, with loss of fiber organization. LC1 provided a partial and visible protection. The dose-dependent protection afforded by LC1 was paralleled by lower values of myeloperoxidase activity, tumor necrosis factor a, and macrophage inflammatory protein-1a. The functional link between migrated leukocytes and the myocardial damage was confirmed by electron and light microscopy, and a significantly lower number of extravasated leukocytes was counted in the group of rats treated with LC1 (50 microg). In conclusion, we demonstrate for the first time that LC1 reduces the leukocyte-dependent myocardial damage associated with an ischemia-reperfusion procedure.
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PMID:Lipocortin 1 reduces myocardial ischemia-reperfusion injury by affecting local leukocyte recruitment. 1102 69

To study possible mechanisms for metallothionein (MT) inhibition of ischemia-reperfusion-induced myocardial injury, cardiomyocytes isolated from MT-overexpressing transgenic neonatal mouse hearts and nontransgenic controls were subjected to 4 h of hypoxia (5% CO2-95% N2, glucose-free modified Tyrode's solution) followed by 1 h of reoxygenation in MEM + 20% fetal bovine serum (FBS) (5% CO2-95% air), and cytochrome c-mediated caspase-3 activation apoptotic pathway was determined. Hypoxia/reoxygenation-induced apoptosis was significantly suppressed in MT-overexpressing cardiomyocytes, as measured by both terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling and annexin V-FITC binding. In association with apoptosis, mitochondrial cytochrome c release, as determined by Western blot, was observed to occur in nontransgenic cardiomyocytes. Correspondingly, caspase-3 was activated as determined by laser confocal microscopic examination with the use of FITC-conjugated antibody against active caspase-3 and by enzymatic assay. The activation of this apoptotic pathway was significantly inhibited in MT-overexpressing cells, as evidenced by both suppression of cytochrome c release and inhibition of caspase-3 activation. The results demonstrate that MT suppresses hypoxia/reoxygenation-induced cardiomyocyte apoptosis through, at least in part, inhibition of cytochrome c-mediated caspase-3 activation.
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PMID:Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes. 1129 33

Astrocytes participate in a wide variety of important physiological processes and pathological insults, including ischemia. Information on the mechanism of astroglial injury and death during ischemic insult, however, is scarce. In this study, we investigated the mode of astrocytic cell death using an in vitro ischemic model. Cultured astrocytes exhibited several distinct morphological and biochemical features of apoptosis under ischemia. At 4 h of ischemia, Annexin V staining demonstrated an early commitment of some astrocytes to apoptosis. Condensed nuclei became visible from 4 h and the number increased with ischemic incubation time. Electron microscopy showed compacted and segregated chromatin along the edges of nuclear membranes. The number of TUNEL-positive nuclei and the degree of DNA laddering increased with ischemic incubation. Caspase-3, but not caspase-1, activity was increased in ischemia-injured astrocytes. Swollen mitochondria and vacuoles found in some cells with chromatin condensation indicated that these apoptotic-like cells might die of necrosis. The results imply that astrocytes are capable of undergoing apoptosis without the presence of other cell types, such as neurons. Ischemia can induce apoptosis in astrocytes contributing to the pathogenesis of ischemic injury in the CNS.
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PMID:Ischemia-induced apoptosis in primary cultures of astrocytes. 1146 Feb 68

With the use of markers of sarcolemmal membrane permeability, cardiomyocyte models of ischemic injury have primarily addressed necrotic death during ischemia. In the present study, we used annexin V-propidium iodide staining to examine apoptosis and necrosis after simulated ischemia and simulated reperfusion in rat ventricular myocytes. Annexin V binds phosphatidylserine, a phosphoaminolipid thought to be externalized during apoptosis or programmed cell death. Propidium iodide is a marker of cell necrosis. Under baseline conditions, <1% of cardiomyocytes stained positive for annexin V. After 20 or 60 min of simulated ischemia, there was no increase in annexin V staining, although 60-min simulated ischemia resulted in significant propidium iodide staining. Twenty minutes of simulated ischemia, followed by 20 or 60 min of simulated reperfusion, resulted in 8-10% of myocytes staining positive for annexin V. Annexin V-positive cells retained both rod-shaped morphology and contractile function but exhibited the decreased cell width indicative of cell shrinkage. Baseline mitochondrial free Ca2+ (111 +/- 14 nM) was elevated in reperfused annexin V-negative cells (214 +/- 22 nM), and further elevated in annexin V-positive myocytes (382 +/- 9 nM). After 60 min of simulated reperfusion, caspase-3-like activity was observed in approximately 3% of myocytes, which had a rounded appearance and membrane blebs. These results suggest that the use of annexin V after simulated ischemia-reperfusion uncovers a population of cardiomyocytes whose characteristics appear to be consistent with cells undergoing apoptosis.
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PMID:Annexin V staining during reperfusion detects cardiomyocytes with unique properties. 1166 53

Apoptosis contributes to myocardial cell death during ischemia and reperfusion, especially during reperfusion. Growth factor "survival" signaling attenuates apoptosis. We therefore examined the effects of transforming growth factor-beta1 (TGF-beta1) on reperfusion injury and assessed the role of p42/p44 MAPK signaling in TGF-beta1-induced protection. Rat ventricular myocytes were subjected to hypoxia and reoxygenation. TGF-beta1 (0.2 ng/ml) was applied to cells during reoxygenation and the extent of apoptosis was determined by TUNEL and annexin V binding assays. Further studies were conducted in intact rat hearts subjected to regional ischemia and reperfusion. TGF-beta1 (0.2 ng/ml) was perfused during early reperfusion. In cells, incubation with TGF-beta1 (0.2 ng/ml) during reoxygenation attenuated the extent of cell membrane damage (trypan blue uptake) and also reduced the numbers of TUNEL-and annexin V-positive cells. Reduction of apoptosis was abrogated by PD98059 (5 microM), an inhibitor of p42/p44 MAPK activation. TGF-beta1 activated p42/p44 MAPK transiently in normoxic myocytes. When intact hearts received TGF-beta1 (0.2 ng/ml) during early reperfusion, infarct size was reduced from 39.4 +/- 3.1% to 17.3 +/- 3.1% (p < 0.01). This protective action of TGF-beta1 was abrogated by PD98059. These studies are the first to show that TGF-beta attenuates cardiac myocyte apoptosis during early reperfusion and limits infarct size through p42/p44 MAPK activation.
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PMID:Cardioprotective effects of transforming growth factor-beta1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK. 1170 97


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