Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postischemic endothelial dysfunction may occur as a result of the effects of endogenous oxidants like hydrogen peroxide. Since endothelium-dependent vasodilator function may be affected by pHi, the effect of hydrogen peroxide on endothelial pHi was examined. Hydrogen peroxide (100 micromol/L for 10 minutes) decreased pHi from 7.24+/-0.01 to 7.02+/-0.02 and inhibited recovery from an ammonium chloride-induced intracellular acid load in carboxy SNARF 1 (c-SNARF 1)-loaded human aortic endothelial cells in bicarbonate-free solution. Prior inhibition of Na+/H+ exchange with 5-(N-ethyl-N-isopropyl)amiloride (10 micromol/L), by removal of extracellular Na+, or by glycolytic inhibition with iodoacetic acid blocked the subsequent effect of hydrogen peroxide on pHi. A 2-minute exposure to 100 micromol/L H2O2 decreased intracellular ATP levels by approximately 40%; this was prevented by 3-aminobenzamide and nicotinamide (1 mmol/L each), inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase. Both 3-aminobenzamide and nicotinamide significantly inhibited the hydrogen peroxide-induced intracellular acidification and the effect of hydrogen peroxide on recovery from an intracellular acid load. Hydrogen peroxide decreases pHi in human endothelial cells by inhibiting Na+/H+ exchange. This appears to be mediated by activation of the DNA repair enzyme poly(ADP-ribose) polymerase and subsequent depletion of intracellular ATP. Since a decrease in pHi in this range may alter the activity of NO synthase or affect the synthesis of vasodilator prostaglandins, the effect of hydrogen peroxide on the endothelial Na+/H+ exchanger may be important in the pathogenesis of postischemic endothelial dysfunction.
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PMID:Hydrogen peroxide decreases pHi in human aortic endothelial cells by inhibiting Na+/H+ exchange. 974 60

Nitric oxide (NO) that is produced by inducible NO synthase (iNOS) in glial cells is thought to contribute significantly to the pathogenesis of multiple sclerosis. Oligodendrocytes can be stimulated to express iNOS by inflammatory cytokines, which are known to accumulate in the multiple sclerotic brain. The potentially pathological levels of NO produced under these circumstances can target a wide spectrum of intracellular components. We hypothesized that one of the critical targets for damage that leads to disease is mtDNA. In this study, we found that cytokines, in particular a combination of tumor necrosis factor-alpha (50 ng/ml) and IFNgamma (25 ng/ml), cause elevated NO production in primary cultures of rat oligodendrocytes. Western blot analysis revealed a strong enhancement of iNOS expression 48 h after cytokine treatment. Within the same time period, NO-mediated mtDNA damage was shown by Southern blot analysis and by ligation-mediated PCR. Targeting the DNA repair enzyme human 8-oxoguanine DNA glycosylase (hOGG1) to the mitochondria of oligodendrocytes had a protective effect against this cytokine-mediated mtDNA damage. Moreover, it was shown that mitochondrial transport sequence hOGG1-transfected oligodendrocytes had fewer apoptotic cells compared with cells containing vector only following treatment with the cytokines. Subsequent experiments revealed that targeting hOGG1 to mitochondria reduces the activation of caspase-9, showing that this recombinant protein works to reduce apoptosis that is occurring through a mitochondria-based pathway.
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PMID:Cytokines induce nitric oxide-mediated mtDNA damage and apoptosis in oligodendrocytes. Protective role of targeting 8-oxoguanine glycosylase to mitochondria. 1581 55