Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen peroxide (H(2)O(2)) and its metabolites have been shown to exert complex effects on the cardiac muscle during cardiac ischemia/reperfusion. The aim of the present study, by perfusing H(2)O(2) or/and different scavengers of oxygen free radicals (OFRs) into the human atrium, is to characterize the electropharmacological effects of H(2)O(2) and explore its possible underlying mechanism. Atrial tissues obtained from the heart of 19 patients undergoing corrective cardiac surgery were used. Transmembrane action potentials were recorded using the conventional microelectrode technique, and contraction of atrial fibers was evaluated in normal [K](o) (4 mM) in the absence and presence of tested agents. H(2)O(2) (30 micro M-3 mM) had a biphasic effect on the contractile force (an increase, followed by a decrease), reduced the 0-phase depolarizing slope (dV/dt), and prolonged the action potential duration (APD) in a concentration-dependent manner. However, even at a concentration as high as 3 mM, H(2)O(2) did not influence diastolic membrane potential (DMP). Pretreatment with N-(mercaptopropionyl)-glycine (N-MPG), a specific scavenger of the. OH free radical, significantly blocked the 3 mM H(2)O(2)-induced electromechanical changes, while the pretreatment with L-methionine (L-M), a specific scavenger of HOCl free radical, did not. Our data suggests that the toxic effects of H(2)O(2) are caused mainly through the generation of. OH, which is attributed to the electropharmacological inhibitory effects seen in the human atrium.
 ...
PMID:Possible underlying mechanism for hydrogen peroxide-induced electromechanical suppression in human atrial myocardium. 1268 31

The precise molecular basis for myocardial stunning remains unresolved, but protein damage within the myofibril is a likely mechanism. We used two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) to identify protein modifications in stunned myocardium. In isolated, perfused rabbit hearts, low-flow ischemia (1 ml/min) and reperfusion resulted in impaired left-ventricular function (rate-pressure product (RPP) after 15-min ischemia: 65 +/- 5% pre-ischemia). We have characterised the sequence of ventricular myosin-regulatory light chain (MLC-2, 18 kDa) in rabbit myocardium and identified two non-phosphorylated (P(1) and P(2)) and two phosphorylated (P(3) and P(4) at Ser-14) isoelectric point variants. MS revealed that the acidic isoelectric point post-translational modification of P(1) and P(3), resulting in P(2) and P(4) respectively, was due to deamidation of asparagine to aspartate at residue 13, adjacent to Ser-14 phosphorylation site. After 15-min ischemia and reperfusion, a 15-kDa MLC-2 fragment was detected (MLC-2(14-165)), resulting from N-terminal cleavage between Asn/Asp-13 and Ser-14 of non-phosphorylated MLC-2, which accounted for 9.8% of visible non-phosphorylated MLC-2. Subsequent 2-DE of subcellular fractions showed that the fragment was lost from the myofilament. Treatment with an OH radical scavenger, N-(2-mercaptopropionyl) glycine (MPG, 3 mmol/l), preserved contractile function (RPP: 106 +/- 9% pre-ischemia) and prevented cleavage of MLC-2. Proteolytic damage to MLC-2, related to presence of OH radicals during reperfusion, correlates with myocardial stunning and may contribute to impaired contractility.
 ...
PMID:Modifications of myosin-regulatory light chain correlate with function of stunned myocardium. 1281 74

Although the contribution of reactive oxygen species to myocardial ischemia is well recognized, the possible intracellular targets, especially at the level of myofibrillar proteins (MP), are not yet fully characterized. To assess the maximal extent of oxidative degradation of proteins, isolated rat hearts were perfused with 1 mM H(2)O(2). Subsequently, the MP maximally oxidative damage was compared with the effects produced by 1) 30 min of no-flow ischemia (I) followed in other hearts by 3 min of reperfusion (I/R); and 2) I/R in the presence of a potent antioxidant N-(2-mercaptopropionyl)glycine (MPG). Samples from the H(2)O(2) group electrophoresed under nonreducing conditions and probed with actin, desmin, or tropomyosin monoclonal antibodies showed high-molecular mass complexes indicative of disulfide cross-bridges along with splitting and thickening of tropomyosin and actin bands, respectively. Only these latter changes could be detected in I/R samples and were prevented by MPG. Carbonyl groups generated by oxidative stress on MP were detected by Western blot analysis (oxyblot) under optimized conditions. The analyses showed one major band corresponding to oxidized actin, the density of which increased 1.2-, 2.8-, and 6.8-fold in I, I/R, and H(2)O(2) groups, respectively. The I/R-induced increase was significantly reduced by MPG. In conclusion, oxidative damage of MP occurs on reperfusion, although at a lower extent than in H(2)O(2) perfused hearts, whereas oxidative modifications could not be detected in ischemic hearts. Furthermore, the inhibition of MP oxidation by MPG might underlie the protective efficacy of antioxidants.
 ...
PMID:Evidence of myofibrillar protein oxidation induced by postischemic reperfusion in isolated rat hearts. 1476 72

Whereas previous studies have shown that opening of the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel protects the adult heart against ischemia-reperfusion injury, it remains to be established whether this mechanism also operates in the developing heart. Isolated spontaneously beating hearts from 4-day-old chick embryos were subjected to 30 min of anoxia followed by 60 min of reoxygenation. The chrono-, dromo-, and inotropic disturbances, as well as alterations of the electromechanical delay (EMD), reflecting excitation-contraction (E-C) coupling, were investigated. Production of reactive oxygen species (ROS) in the ventricle was determined using the intracellular fluorescent probe 2',7'-dichlorofluorescin (DCFH). Effects of the specific mitoK(ATP) channel opener diazoxide (Diazo, 50 microM) or the blocker 5-hydroxydecanoate (5-HD, 500 microM), the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 microM), the antioxidant N-(2-mercaptopropionyl)glycine (MPG, 1 mM), and the PKC inhibitor chelerythrine (Chel, 5 microM) on oxidative stress and postanoxic functional recovery were determined. Under normoxia, the baseline parameters were not altered by any of these pharmacological agents, alone or in combination. During the first 20 min of postanoxic reoxygenation, Diazo doubled the peak of ROS production and, interestingly, accelerated recovery of ventricular EMD and the PR interval. Diazo-induced ROS production was suppressed by 5-HD, MPG, or L-NAME, but not by Chel. Protection of ventricular EMD by Diazo was abolished by 5-HD, MPG, L-NAME, or Chel, whereas protection of the PR interval was abolished by L-NAME exclusively. Thus pharmacological opening of the mitoK(ATP) channel selectively improves postanoxic recovery of cell-to-cell communication and ventricular E-C coupling. Although the NO-, ROS-, and PKC-dependent pathways also seem to be involved in this cardioprotection, their interrelation in the developing heart can differ markedly from that in the adult myocardium.
 ...
PMID:mitoKATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways. 1555 May 17

Reactive oxygen species (ROS) are known to mediate the protection conferred by the opening of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) during ischemia in heart, but this has not been demonstrated in brain. The present study examined whether ROS mediate the neuroprotection conferred by a mitoK(ATP) opener during ischemia in rat hippocampal slices. Ischemia was simulated by oxygen and glucose deprivation. The direct current potential and population spike were recorded in the stratum pyramidale of the CA1 region, and lactate dehydrogenase (LDH) efflux into the medium was assayed. ROS generation was measured spectrophotofluorometrically. Pretreatment of slices with diazoxide (DIA, 300 microM), a mitoK(ATP) opener, (i) prolonged the latency to ischemic depolarization and decreased its amplitude, (ii) delayed the onset of population spike disappearance and enhanced its recovery after reperfusion, (iii) decreased LDH efflux and (iv) increased ROS levels. The effects induced by DIA were attenuated by 5-hydroxydecanoic acid (200 microM), a mitoK(ATP) blocker. Pretreatment with N-2-mercaptopropionyl glycine (MPG, 500 microM), a ROS scavenger, also abrogated the effects induced by DIA, while treatment with MPG alone had no effect during normoxia and ischemia. These results indicate that ROS participate in the neuroprotection conferred by a mitoK(ATP) opener during ischemia.
 ...
PMID:Reactive oxygen species mediate the neuroprotection conferred by a mitochondrial ATP-sensitive potassium channel opener during ischemia in the rat hippocampal slice. 1585 88

Reactive oxygen species (ROS)-mediated signaling is implicated in early ischemic preconditioning (PC). A NOX-2-containing NADPH oxidase is a recognized major source of ROS in cardiac myocytes, whose activity is augmented by preconditioning mimetics, such as angiotensin II. We hypothesized that this oxidase is an essential source of ROS in PC. Hearts from wild-type (WT) and NOX-2 knockout (KO) mice were Langendorff perfused and subjected to 35 min ischemia/reperfusion with or without preceding PC or drug treatment. Infarct size was measured by triphenyl tetrazolium chloride staining, and NADPH oxidase activity by lucigenin chemiluminescence. PC significantly attenuated infarct size in WT (26+/-2% vs. control, 38+/-2%, P<0.05) yet was ineffective in KO hearts (33+/-3% vs. control, 34+/-3%). Concomitantly, PC significantly increased NADPH oxidase activity in WT (+41+/-13%; P<0.05), but not in KO (-5+/-18%, P=NS). The ROS scavenger MPG (N-2-mercaptopropionyl glycine, 300 micromol/L) abrogated PC in WT (39+/-2% vs. control, 33+/-1%). CCPA (2-chloro N6 cyclopentyl adenosine, 200 nmol/L), a putative ROS-independent PC trigger, significantly attenuated infarct size in WT, MPG-treated WT and KO hearts (24+/-2, 23+/-1, and 20+/-3%, respectively, P<0.05). Furthermore, CCPA did not augment NADPH oxidase activity over control (+22+/-11%, P=NS). Inhibition of protein kinase C (PKC) with chelerythrine (CHE, 2 micromol/L) completely abrogated both PC (38+/-2% vs. CHE alone, 35+/-2%) and associated increases in oxidase activity (+3+/-10%, P=NS). PKC-dependent activation of a NOX-2-containing NADPH oxidase is pivotally involved in early ischemic PC. However, adenosine receptor activation can trigger a ROS and NOX-2 independent PC pathway.
 ...
PMID:Pivotal role of NOX-2-containing NADPH oxidase in early ischemic preconditioning. 1623 99

Tachycardia with rapid ventricular pacing induces delayed preconditioning against arrhythmias secondary to coronary artery occlusion (CAO) and reperfusion (CAR) but its effects on myocardial stunning remains unknown. Accordingly, we investigated whether delayed preconditioning with ventricular pacing develops against myocardial stunning and whether this phenomenon is triggered by reactive oxygen species. Eight chronically instrumented conscious dogs underwent three experimental sequences in a random order a week apart: (a) 10-min CAO (coronary occluder) followed by CAR, i.e. "Control" sequence; (b) pacing (right ventricular electrodes, 240 beats/min during 40 min) performed 24 h before the 10-min CAO, i.e. "PC" sequence; and (c) N-(2-mercaptopropionyl)-glycine (MPG, 100 mg/kg per h) administered concomitantly to pacing and 10-min CAO performed 24 h later, i.e. "PC+MPG" sequence. During "Control", left ventricular (LV) wall thickening (%, sonomicrometry) was dramatically reduced during CAO (-96 +/- 5% from 2.9 +/- 0.4 mm) and remained depressed during CAR demonstrating myocardial stunning. During "PC", LV wall thickening was not altered by pacing per se and was similarly decreased during CAO vs. "Control". However, during CAR, LV wall thickening was improved vs. "Control" (e.g. -24 +/- 5% and -8 +/- 4% from corresponding baseline for "PC" and "Control", respectively at 2 h-CAR; P<0.05), demonstrating delayed preconditioning. Administration of MPG during pacing (n=5) abolished the beneficial effects of pacing. Myocardial lactate extraction and transmural distribution of regional myocardial blood flow (fluorescent microspheres) were not modified, by pacing. In conclusion, tachycardia with rapid ventricular pacing induces delayed cardioprotection against myocardial stunning. The production of reactive oxygen species independently from ischemia appears to be a major trigger for this phenomenon.
 ...
PMID:Rapid ventricular pacing induces delayed cardioprotection against myocardial stunning. 1624 41

We have previously demonstrated that tumor necrosis factor alpha (TNFalpha), a cytokine known to be induced by ischemia, independently promotes preconditioning in part via ceramide generation. As reactive oxygen species (ROS) signaling is evoked by ischemic preconditioning, by TNFalpha and by ceramide we reasoned that ceramide-induced preconditioning is ROS-mediated. Fibroblastic L-cells were subjected to 8 hours simulated ischemia and were preconditioned by pretreatment with cell permeable c2 ceramide (1 microM) with or without the antioxidant N-mercaptopropionyl glycine (MPG; 1 mM). Pretreatment with ceramide reduced lactate dehydrogenase release at the end of the simulated ischemia but this cytoprotective effect was lost in the presence of MPG. Concurrent temporal ROS generation was measured using confocal microscopy on cells stained with dichlorofluorescein diacetate (DCF-DA). Ceramide increased ROS production after 30 minutes and this induction was decreased by MPG. Incubation of ceramide with cyclooxygenase-2 inhibitor, NS 398 (10 microM), or with a mitochondrial respiratory chain inhibitor, rotenone (10 microM) reduced the cytoprotective effect of ceramide in parallel with a partial diminution in ROS generation. In contrast, inhibition of other ROS-producing systems including nitric oxide synthase, xanthine oxidase, or NADPH oxidase failed to modulate ceramide-induced cytoprotection. Collectively, these data demonstrate that ceramide induces a cell survival program through ROS signaling activated, in part, via cyclooxygenase and the mitochondrial respiratory chain.
 ...
PMID:Ceramide attenuates hypoxic cell death via reactive oxygen species signaling. 1642 1

Heat shock protein 27 (Hsp27) and alpha B-crystallin (alphaBC) are small heat shock proteins that stabilize the myofilament during stress. We utilized two-dimensional gel electrophoresis (2-DE), phospho-fluorescence staining, titanium dioxide (TiO(2)) phosphopeptide purification and mass spectrometry (MS) to fully characterize isoelectric point (pI) variants of Hsp27 and alphaBC in rabbit myocardium subjected to brief ischemia/reperfusion (I/R) injury. Four variants of Hsp27 were detected, two of which were phosphorylated: HSP1 (at three sites, Ser15, Ser78 and Ser82) and HSP2 (at Ser15 and Ser82, but not Ser78). Three variants of alphaBC were detected: alphaBC1 was phosphorylated (at Ser59 alone) and alphaBC2 was deamidated (at Asn146). No modifications were found in the remaining variants. Both phospho-Hsp27 variants increased in abundance in tissue subjected to brief I/R injury (15 min I/60 min R) and ischemia without subsequent reflow (15I/0R), and these increases were not affected by addition of the potent antioxidant, N-(2-mercaptopropionyl) glycine (MPG; 15I/60R + MPG and 15I/0R + MPG). Abundance of native and phosphorylated (but not deamidated) alphaBC was elevated following 15I/60R; however, these increases were ameliorated by the presence of MPG, and did not occur in tissue subjected to 15I/0R. Both phospho-Hsp27 variants and phospho-alphaBC translocated to the myofilament following 15I/60R. Increased myofilament association of phospho-Hsp27 was not influenced by MPG, and there was a greater proportion of HSP2 than HSP1 in this fraction. MPG inhibited phospho-alphaBC translocation and increased alphaBC association with the myofilament did not occur during 15I/0R. Increased phosphorylation of Hsp27 is ischemia-specific and not influenced by reactive oxygen species (ROS), while increased expression and phosphorylation of alphaBC are ROS-dependant.
 ...
PMID:Ischemia-specific phosphorylation and myofilament translocation of heat shock protein 27 precedes alpha B-crystallin and occurs independently of reactive oxygen species in rabbit myocardium. 1667 50

We showed recently that mitochondrial ATP-dependent K(+) channel (mitoK(ATP)) opening is required for the inotropic response to ouabain. Because mitoK(ATP) opening is also required for most forms of cardioprotection, we investigated whether exposure to ouabain was cardioprotective. We also began to map the signaling pathways linking ouabain binding to Na(+)-K(+)-ATPase with the opening of mitoK(ATP). In Langendorff-perfused rat hearts, 10-80 microM ouabain given before the onset of ischemia resulted in cardioprotection against ischemia-reperfusion injury, as documented by an improved recovery of contractile function and a reduction of infarct size. In skinned cardiac fibers, a ouabain-induced protection of mitochondrial outer membrane integrity, adenine nucleotide compartmentation, and energy transfer efficiency was evidenced by a decreased release of cytochrome c and preserved half-saturation constant of respiration for ADP and adenine nucleotide translocase-mitochondrial creatine kinase coupling, respectively. Ouabain-induced positive inotropy was dose dependent over the range studied, whereas ouabain-induced cardioprotection was maximal at the lowest dose tested. Compared with bradykinin (BK)-induced preconditioning, ouabain was equally efficient. However, the two ligands clearly diverge in the intracellular steps leading to mitoK(ATP) opening from their respective receptors. Thus BK-induced cardioprotection was blocked by inhibitors of cGMP-dependent protein kinase (PKG) or guanylyl cyclase (GC), whereas ouabain-induced protection was not blocked by either agent. Interestingly, however, ouabain-induced inotropy appears to require PKG and GC. Thus 5-hydroxydecanoate (a selective mitoK(ATP) inhibitor), N-(2-mercaptopropionyl)glycine (MPG; a reactive oxygen species scavenger), ODQ (a GC inhibitor), PP2 (a src kinase inhibitor), and KT-5823 (a PKG inhibitor) abolished preconditioning by BK and blocked the inotropic response to ouabain. However, only PP2, 5-HD, and MPG blocked ouabain-induced cardioprotection.
 ...
PMID:Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. 1709 31


<< Previous 1 2 3 4 5 6 Next >>