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Query: UNIPROT:P06889 (Mol)
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The development of H2O2-induced changes in membrane potentials, membrane currents and corresponding contractile activity (shortening) were studied in rat and guinea-pig ventricular myocytes using the suction-pipette whole-cell clamp method. The cells exhibited a different sensitivity to 30 microM H2O2 in terms of time development of the changes, which were fully irreversible. The observed changes are described in three phases: (1) prolongation of action potential duration (APD) accompanied by increased contractility. With a prolonged exposure, the increased APD was accompanied by early afterdepolarizations (EADs), delayed afterdepolarizations (DADs) and aftercontractions. The changes in APD and the EADs were fully and permanently abolished by tetrodotoxin (TTX) but not by nifedipine, while the DADs and aftercontractions were abolished by ryanodine. These changes preceded phase (2), which was characterized by APD shortening, a decrease in contractility, membrane depolarization, single or multiple extrasystoles, or steady spontaneous activity; this phase could not be prevented by any of the above pharmacological interventions and resulted in a final phase (3) characterized by full depolarization and inexcitability. All the above changes were prevented by intracellular application of iron chelator-deferoxamine, indicating that .OH generated intracellularly in the presence of Fe3+ induces the observed changes. The examination of membrane currents indicated that the increased APD may be due to an increase in the TTX-sensitive Na+ current as well as to the decreased delayed current, while L-type Ca2+ channels appear to be unaffected. The shortening of APD during the second phase was associated with a large increase in the delayed K+ current. The increased contractility in the first stage appears to be due to increased sarcolemmal Ca2+ influx via Na(+)-Ca2+ exchange (among other possible mechanisms), leading to a loading of sarcoplasmic reticulum that eventually results in Ca2+ overload and functional failure.
J Mol Cell Cardiol 1991 Aug
PMID:Alterations in electrical and contractile behavior of isolated cardiomyocytes by hydrogen peroxide: possible ionic mechanisms. 194 91

Although cardiac dysfunction due to ischemia-reperfusion injury is considered to involve oxygen free radicals, the exact manner by which this oxidative stress affects the myocardium is not clear. As the occurrence of intracellular Ca2+ overload has been shown to play a critical role in the genesis of cellular damage due to ischemia-reperfusion, this study was undertaken to examine whether oxygen free radicals are involved in altering the sarcolemmal Ca2(+)-transport activities due to reperfusion injury. When isolated rat hearts were made globally ischemic for 30 min and then reperfused for 5 min, the Ca2(+)-pump and Na(+)-Ca2+ exchange activities were depressed in the purified sarcolemmal fraction; these alterations were prevented when a free radical scavenger enzymes (superoxide dismutase plus catalase) were added to the reperfusion medium. Both the Ca2(+)-pump and Na(+)-Ca2+ exchange activities in control heart sarcolemmal preparations were depressed by activated oxygen-generating systems containing xanthine plus xanthine oxidase and H2O2; these changes were prevented by the inclusion of superoxide dismutase and catalase in the incubation medium. These results support the view that oxidative stress during ischemia-reperfusion may contribute towards the occurrence of intracellular Ca2+ overload and subsequent cell damage by depressing the sarcolemmal mechanisms governing the efflux of Ca2+ from the cardiac cell.
Mol Cell Biochem 1990 Dec 20
PMID:Alterations in cardiac membrane Ca2+ transport during oxidative stress. 196 45

Exposure to oxidants permeabilizes cell membranes and liberates unesterified fatty acids (UFA) in a variety of cell types, including endothelial cells. Products of phospholipase activity, particularly UFA and lysophosphatides, possess potent detergent-like properties, and we postulated that oxidant injury might be mediated by the accumulation of these toxic phospholipase products. Several radiolabels were incorporated into defined positions in the phospholipids of cultured, confluent bovine pulmonary endothelial cells (BPAEC). The release of radiolabeled fatty acids and the accumulation of cell-associated phospholipase products were measured and compared to a standard cytotoxicity assay (51Cr release) in response to an oxidant stress, in this case 0.1 to 10 mM hydrogen peroxide (H2O2). H2O2 caused time- and dose-dependent 51Cr release as well as liberation of saturated ([14C]stearic acid) and unsaturated ([3H]arachidonic acid) fatty acids and the accumulation of phospholipase A2 and C products. The ability of BPAEC to incorporate UFA into complex phospholipids was shown to be severely impaired in the presence of H2O2. Further studies showed that H2O2 caused depletion of BPAEC adenosine triphosphate (ATP) content to undetectable levels, and that the depletion of cellular ATP by iodoacetic acid induced substantial release of [3H]arachidonic acid but not [14C]stearic acid from BPAEC. This finding suggests that release of UFA in response to an oxidant stress may be due in part to a defect in ATP-dependent reacylation pathways and need not reflect any increase in phospholipase activities. Also unsaturated fatty acids were found to be toxic to BPAEC upon adding them to supernatants of cultured monolayers.
Am J Respir Cell Mol Biol 1991 May
PMID:Relationship of oxidant-mediated cytotoxicity to phospholipid metabolism in endothelial cells. 202 79

Loss of tritium from [2,4,6 alpha, 7 alpha-3H]estradiol and from [2-3H]estradiol during their conversion into polyestradiol (PEL) by horseradish peroxidase/H2O2 and the NMR spectrum of PEL permethyl ether suggest that PEL is composed of two or more different subunits, each formed by the joining of four molecules of estradiol with the loss of five hydrogen atoms from positions 2 and 4 and of three phenolic hydrogens leading to the formation of one C-C bond and three C-O bonds. At very low concentrations of estradiol the main reaction products were monomers; this is attributed to the initial formation of transient tetraestradiols which combine with water at high dilution and with themselves at low dilution. Association of the monomeric products to oligomers occurred on a Sephadex G-50 column and was readily reversed in phosphate buffer. In aqueous solution PEL underwent non-covalent changes induced by heat, time and electrolytes, and affecting its solubility, u.v. absorbance, extraction by organic solvents and ability to bind estradiol.
J Steroid Biochem Mol Biol 1991 Jul
PMID:Products of estradiol/peroxidase interaction; their structural features and biopolymeric character. 206 68

The therapeutic effect of ebselen has been linked to its peroxidase activity. In the present study, the peroxidase activity of ebselen toward H2O2 with the endogenous thiols GSH and dihydrolipoate [L(SH)2] as cofactors was determined. When GSH was used, peroxide removal was described by a ter uni ping pong mechanism with Dalziel coefficients for GSH and H2O2 of 0.165 +/- 0.011 and 0.081 +/- 0.005 mM min, respectively. When L(SH)2 was used, peroxidase activity was independent of the concentration of L(SH)2 in the concentration range studied (5 microM to 2 mM) and peroxide removal was only dependent on the concentration of H2O2 and ebselen, with the second-order rate constant being 12.3 +/- 0.8 mM-1 min-1. To elucidate the difference between GSH and L(SH)2, the molecular mechanism of the peroxidase activity of ebselen was investigated, using UV spectrophotometry, high pressure liquid chromatography, 77Se NMR, and mass spectrometry. GSH was found to react quickly with ebselen to give a selenenyl sulfide, an adduct of GSH to ebselen. Subsequently, the GSH-selenenyl sulfide is converted into the diselenide of ebselen. Finally the diselenide reacts with a peroxide and ebselen is regenerated. The formation by GSH of the diselenide from the GSH-selenenyl sulfide of ebselen is slow and linearly dependent on the concentration of free thiol; however, no net consumption of GSH was observed. Furthermore, it is likely that a selenol is an intermediate in diselenide formation. After reaction between ebselen and L(SH)2 the diselenide of ebselen was immediately detected. The fast formation of the diselenide with L(SH)2 versus the slow formation of the diselenide with GSH accounts for our observation that L(SH)2 is a better cofactor than GSH in the peroxidase activity of ebselen. Our results suggest that the interaction between ebselen and L(SH)2 might be of major importance in the mechanism by which ebselen exerts its therapeutic effect.
Mol Pharmacol 1990 Mar
PMID:Mechanism of the reaction of ebselen with endogenous thiols: dihydrolipoate is a better cofactor than glutathione in the peroxidase activity of ebselen. 210 91

Uptake of neutrophil-derived myeloperoxidase by the macrophage mannose receptor was studied. Rat bone marrow-derived macrophages internalized 75% of [125I]myeloperoxidase through a mannose-specific process. Uptake via the mannose receptor is highly sensitive to treatment with oxidants. Treatment of rat macrophages with 1 mM H2O2 for 30 min resulted in a 94% reduction in uptake of myeloperoxidase. By Percoll gradient fractionation studies, 38% of internalized myeloperoxidase was delivered to the lysosomal compartment during a 15-min chase period, similar to findings for delivery of other ligands for this receptor. Once in the lysosome, the myeloperoxidase remained enzymatically active for several hours, with 50% activity remaining at 8 h. Finally, myeloperoxidase-containing macrophages had an increased capacity to down-regulate their own mannose receptors or receptors on neighboring macrophages, possibly through the myeloperoxidase-mediated production of oxidized halogens. Thus, the macrophage mannose receptor plays a potentially physiologic role in regulating extracellular myeloperoxidase levels. The receptor-mediated uptake may either arm the macrophage to contribute to oxidant-mediated tissue damage or may function to clear extracellular myeloperoxidase during the resolution phase of the inflammatory process.
Am J Respir Cell Mol Biol 1990 Apr
PMID:Clearance of neutrophil-derived myeloperoxidase by the macrophage mannose receptor. 215 73

Hydroxyl radicals (OH.) can be formed in aqueous solution by direct reaction of hydrogen peroxide (H2O2) with ferrous salt (Fenton reaction). OH. damage to deoxyribose, measured as formation of thiobarbituric acid-reactive material, was evaluated at different pHs to study the mechanism of action of classical OH. scavengers. OH. scavenger effect on Fe2+ oxidation was also evaluated in the same experimental conditions. In the absence of OH. scavengers, OH. damage to deoxyribose is higher at acidic compared to neutral and moderately basic pH. At acidic pH deoxiribose is per se able to inhibit Fe2+ oxidation by H2O2. Most of OH. scavengers tested inhibit deoxyribose damage and Fe2+ oxidation in a similar manner: both inhibitions are most relevant at acidic pH and decrease by increasing the pH. These results are not due to OH. scavenger inhibition of Fenton reaction. The influence of pH on the parameters studied appears to be due to the competition of deoxyribose and OH. scavengers for iron. These results suggest the prominent role of iron binding in the degradation of deoxyribose and in the OH. scavenging ability of different compounds. Results obtained with triethylenetetramine, a iron chelator with a low rate constant with OH., confirm that both deoxyribose and the OH. scavengers interact with iron bringing about a site specific Fenton reaction; that the OH. formed at these sites oxidize these molecules to their radical forms which in turn reduce the Fe3+ produced by Fenton reaction. The results presented indicate that most of classical OH. scavengers exert their effect predominantly by preventing the site specific reaction between Fe2+ and H2O2 on the deoxyribose molecule.
Mol Cell Biochem 1990 May 10
PMID:The influence of pH on OH. scavenger inhibition of damage to deoxyribose by Fenton reaction. 216 14

The etiology of mercury-induced porphyrinuria was investigated by testing the hypothesis that mercuric ions (Hg2+) promote free radical-mediated oxidation of reduced porphyrins (porphyrinogens) by compromising the antioxidant potential of endogenous thiols, particularly GSH. Studies in vitro demonstrated that porphyrinogens (uroporphyrinogen and coproporphyrinogen) readily undergo H2O2-dependent oxidization in the presence of Fe3(+)-EDTA and that this action is attenuated by GSH at biologically relevant concentrations (0.5-10 mM). At low concentrations, Hg2+ complexes with GSH in a 1:2 molar ratio to decrease the antioxidant effect of GSH. However, at Hg2+ concentrations approaching saturation-complexation with available GSH, stimulation of porphyrinogen oxidation to 2 to 3 times that mediated by the H2O2/Fe3(+)-dependent system alone is observed. Stimulation of porphyrinogen oxidation by Hg2+ plus GSH increases in a dose-related manner with the concentration of H2O2 in the reaction mixture but is independent of the presence of iron. No porphyrinogen oxidation is observed in reaction mixtures containing H2O2 and either Hg2+ or GSH alone or when Hg+ is substituted for Hg2+. Studies with reactive oxidant scavengers and ESR spectroscopy suggest the participation of free radical species in Hg:GSH-mediated porphyrinogen oxidation. A mechanism involving ligand exchange between Hg2+ and GSH, which leads to formation of GS radicals and subsequent propagation of reactive oxygen-based radical species, is proposed. These studies support the view that Hg2+ both compromises the antioxidant potential of GSH and promotes formation of reactive species via thiol complexation. These findings suggest a mechanistic basis underlying the porphyrinogenic as well as tissue-damaging properties of mercuric ions.
Mol Pharmacol 1990 Aug
PMID:Stimulation of porphyrinogen oxidation by mercuric ion. I. Evidence of free radical formation in the presence of thiols and hydrogen peroxide. 216 5

Isolated myocytes of rat heart, and sealed sarcolemmal vesicles of bovine heart, were used to examine the selectivity of the effects of partially reduced oxygen species (generated by a mixture of xanthine and xanthine oxidase) on cardiac sodium pump and several other ion transporters of the plasma membrane. When myocytes were exposed to xanthine plus xanthine oxidase, there were time-dependent inhibitions of ouabain-sensitive 86Rb+ uptake and (Na+ + K+)-ATPase activity that could be prevented by allopurinol, or by catalase and superoxide dismutase; suggesting the involvements of H2O2 or oxygen free radicals in the inhibition of the pump. This inhibition preceded any significant decrease in cellular ATP or in the number of viable cells. While ouabain increased 45Ca2+ uptake by myocytes as expected, exposure to xanthine plus xanthine oxidase decreased 45Ca2+ uptake; suggesting that the Na+, Ca2(+)-exchanger of the intact myocytes is also inhibited by oxygen metabolites. Simultaneous inhibitions of the pump, the Na+, Ca2(+)-exchange, the Na+, H(+)-exchange, and the Na+, Pi-cotransport activities also occurred in sarcolemmal vesicles that were treated with xanthine plus xanthine oxidase. These findings indicate that inactivations of the sodium pump and other sarcolemmal ion carriers are early events in the oxidant-induced damage to the cardiomyocyte. In the rat heart myocytes, a fraction of (Na+ + K+)-ATPase that seems to be more sensitive to ouabain, was inactivated more rapidly upon exposure of myocytes to xanthine plus xanthine oxidase; raising the possibility of the existence of different pump populations with different sensitivities to extracellularly generated oxygen metabolites.
J Mol Cell Cardiol 1990 Aug
PMID:Studies on the specificity of the effects of oxygen metabolites on cardiac sodium pump. 217 59

The recovery of both contractile performance and metabolic response of rat heart following 1 h of ischemia after equilibration with glucose + insulin (glucose-ischemia) or with pyruvate (pyruvate-ischemia), was tested in normoxic reperfusion in the presence of glucose + insulin, pyruvate, lactate or acetate. In glucose-ischemia only the reperfusion with pyruvate results in a complete recovery of the contractile force (left ventricular pressure, LVP) (170%) and good recovery of high energy phosphate compounds. Lower LVP and tissue energy charge were found in glucose reperfusion and even less in lactate and acetate reperfusion. Disappearance of the IMP accumulated during ischemia is evident only in the pyruvate reperfusion indicating a higher metabolic recovery. On the contrary in pyruvate-ischemia all types of reperfusion tested were effective in reactivating the contractile force (although acetate to a lesser extent); the contractile activity was accompanied by a good recovery of phosphocreatine, ATP, energy charge and by the decrease of IMP. Large decreases of adenine nucleotides and NADP and lower decreases of NAD are observed during ischemia/reperfusion in both systems. Pyruvate-ischemia is quite similar to, if not worse than glucose-ischemia, for all the metabolic parameters considered, but not worse for the possibility of recovery. Some specific effect of pyruvate should be exerted during the ischemic phase. The mechanism of pyruvate protection is discussed in relationship to: (i) the possible activation of pyruvate dehydrogenase, (ii) the activation of NADPH-dependent peroxide scavenging systems, (iii) the direct scavenging action of pyruvate on H2O2.
J Mol Cell Cardiol 1990 Feb
PMID:The protective action of pyruvate on recovery of ischemic rat heart: comparison with other oxidizable substrates. 218 87


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