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)

Prostacyclin is a major vasoprotective molecule. It has multiple physiological functions. Its synthesis is determined by several enzymes of which cyclooxygenase (COX) plays a key role. Two isoforms of COX have been identified. Their expression and regulation are controlled by different mechanisms. COX-1 is constitutively expressed and physiologically important. PGI2 synthesis can be augmented by virus-mediated transfer COX-1 gene. This strategy may be useful for therapy of vascular thrombosis and tissue ischemia.
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PMID:Molecular regulation and augmentation of prostacyclin biosynthesis. 771 68

We examined the effect of reversible ischemia on the transcription of prostaglandin endoperoxide synthase (PGHS-1) and c-fos mRNA in rat cerebral cortex. The level of PGHS-1 mRNA climaxed after 30 min of ischemia whereas transcription of c-fos mRNA peaked after 60 min of postischemic reperfusion. We conclude that cerebral ischemia causes early transcription of PGHS-1, without modulation by the c-fos gene or its translated product.
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PMID:Induction of PGH synthase and c-fos mRNA during early reperfusion of ischemic rat brain. 871 74

Selective phospholipids of synaptic membranes are reservoirs for lipid second messengers. 1-Alkyl-2 arachidonoyl glycero-3-phosphocholine is hydrolyzed by phospholipase A2 (PLA2) into two products: lyso-PAF, which is transacetylated to yield platelet-activating factor (PAF), and free arachidonic acid (20:4), which can undergo oxidative metabolism to eicosanoids. Alternative pathways of PAF synthesis, such as CoA-independent transacylase and the de novo route of synthesis, remain to be explored and compared to the PLA2-dependent route. At low concentrations, PAF is a retrograde messenger of LTP in CA1 hippocampal neurons, and is also a memory enhancer in inhibitor avoidance tasks. PAF enhances excitatory amino acid release in synaptic pairs from primary hippocampal cultures by a presynaptic mechanism. Ischemia and convulsions activate synaptic PLA2. Thus, increased concentrations of PAF promote massive glutamate exocytosis, glutamate receptor activation, and elevated intracellular calcium levels in target cells. As a result, calcium-sensitive cascades are affected. PAF thus had dual roles as a lipid mediator: under physiological conditions it modulates neurotransmitter release, but at high concentrations it becomes neurotoxic. Through an intracellular high affinity binding site, PAF activates the expression of immediate-early genes. Some of these genes encode transcription factors (e.g. zif-268, c-fos), and others encode enzymes (COX-2 or inducible prostaglandin synthase). PAF also activates the expression of metalloproteinases which participate in the remodeling of the extracellular matrix. These effects have been studied in cells in culture as well as in the brain. A PAF antagonist specific for the intracellular binding site inhibits COX-2 expression elicited by a single electroconvulsive shock or vasogenic edema. COX-1, the constitutive prostaglandin synthase, is not induced and is unaffected by the antagonist. Most of the cerebral induction occurs in the hippocampus and results from transcriptional activation. PAF mediated gene expression may be involved in neural plasticity as well as in pathophysiological conditions in which the neural tissue activates repair-injury pathways.
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PMID:Platelet-activating factor in the modulation of excitatory amino acid neurotransmitter release and of gene expression. 890 78

Inhibition of renal vasodilatory prostaglandins (PGs) and secondary ischemia due to inhibition of cyclooxygenase (COX) activity has been suggested as a possible mechanism for development of analgesic-related renal papillary necrosis (RPN) in rats. Recently, it has been shown that COX exists in two related but unique isoforms, COX-1 and COX-2. It is unclear what potential roles these isoforms play in the maintenance of blood flow in the renal papilla or genesis of RPN. We evaluated the effect of 2 papillotoxic agents, including a nonsteroidal anti-inflammatory drug, indomethacin, and a chemical agent, 2-bromoethanamine hydrobromide (2-BEA), on COX-1 and COX-2 in the renal papilla as a means of assessing what changes occur in the expression of these isoforms during the development of RPN. Female Wistar rats approximately 10-17 wk old were treated with either indomethacin (75 mg/kg, single dose, or 10 mg/kg/day for 5 days) or 2-BEA (100 mg/kg/day for 4 days) to create lesions of RPN. In this study, a single 75-mg/kg dose of indomethacin did not cause light microscopic changes of RPN. However, RPN was observed in animals administered indomethacin at 10 mg/kg/day for 1 wk or 2-BEA for 5 days. The immunohistochemical analyses of kidneys showed that both COX-1 and COX-2 were present in the renal papilla of control rats. In animals treated with indomethacin (75 mg/kg), a slight to moderate decrease in both isoforms was observed in essentially normal renal papillary cells within 2 hr, that was followed by an increase in COX-2 immunoreactivity in the renal papilla, macula densa, and thick ascending limbs (both 10- and 75-mg/kg animals). This COX-2 immunoreactivity was greatest in animals with concomitant indomethacin-induced gastrointestinal injury, suggesting a possible role of inflammatory cytokines in COX-2 induction. No changes in the expression of COX isoforms in the intact papilla occurred as a result of 2-BEA; however, cells undergoing degeneration and necrosis lost immunoreactivity to both COX isoforms. The possible mechanism that leads to an initial decrease in COX immunoreactivity in indomethacin-treated animals is not known; however, a reversible ultrastructural change in the papillary cells cannot be ruled out. This decrease in COX isoforms in the renal papilla may contribute to the development of RPN through the loss of vasodilatory PGs.
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PMID:Effect of papillotoxic agents on expression of cyclooxygenase isoforms in the rat kidney. 950 96

Recently, the state of cyclooxygenase (COX) mRNA expression has been reported in an acetic acid-induced chronic gastric ulcer model of mice. However, the time course of COX expression during the developmental stage and the subsequent repair process of acute gastric injury is not well understood at present. In this study, we quantitatively investigated the time course of the level of COX-2 and -1 mRNA expression from the developmental stage through the healing stage in ischemia-reperfusion (I-R)-induced acute gastric damage. COX-2 mRNA was expressed at low or undetectable levels in the normal gastric tissues of control rats. The COX-2 expression between 6 and 48 h following I-R was higher than that of the control gastric tissues; the histological findings were erosion during 1-36 h and transitional appearance from erosion to ulcer at 48 h. The maximum expression of COX-2 mRNA was recorded at 24 h (approximately 200-fold elevation). The COX-2 message was very low or undetectable at 72 h (ulcer stage) and at 96 and 120 h (healing stage of ulcer) after I-R. The level of COX-1 mRNA remained stable through all stages of acute gastric damage. These results are potentially useful for understanding the role of COX and evaluating the effects of drugs on expression of COX at various stages of acute gastric injury.
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PMID:Levels of cyclooxygenase-1 and -2 mRNA expression at various stages of acute gastric injury induced by ischemia-reperfusion in rats. 952 28

Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 microM H2O2 for 10 min or doxorubicin at 10 and 100 micrograms/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-kappaB-2 but not the NF-kappaB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation.
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PMID:Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. 998 50

The use of non steroidal anti-inflammatory drugs as analgesic or anti-inflammatory agents is primarily limited by their toxicity to the gastrointestinal tract. Two strategies have been developed recently in order to improve the safety of these drugs. The first approach is the linking of a nitric oxide-releasing moiety to the available compounds. The rationale is that nitric oxide may prevent non steroidal anti-inflammatory drugs-induced ulcerations by preventing mucosal ischemia. The second approach is based on the discovery of two isoforms (COX-1 and COX-2) of the cyclo-oxygenase enzyme. It was hypothesized that the constitutively expressed COX-1 isoenzyme leads to the synthesis of prostaglandins with homeostatic functions whereas COX-2 is merely responsible for the production of prostaglandins mediating pain, fever and inflammation. Accordingly, selective COX-2 inhibitors have been developed. Clinical trials indicate that these compounds are roughly as effective as the available non steroidal anti-inflammatory agents without causing acute gastrointestinal damage. There is some evidence that both COX-1 and COX-2 isoforms are involved in the production of prostaglandins associated with inflammation and homeostatic functions. Finally, the true benefit/risk ratio of these new non steroidal anti-inflammatory drugs remains to be assessed.
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PMID:[New nonsteroidal anti-inflammatory agents: nitric oxide donors and selective cyclooxygenase-2 inhibitors]. 1048 Jan 84

In the newborn, cyclooxygenase (COX)-derived products play an important role in the cerebrovascular dysfunction after ischemia-reperfusion (I/R). We examined effects of I/R on expression of COX-1 and COX-2 isoforms in large cerebral arteries of anesthetized piglets. The circle of Willis, the basilar, and the middle cerebral arteries were collected from piglets at 0.5-12 h after global ischemia (2.5-10 min, n = 50), hypoxia (n = 3), or hypercapnia (n = 2) and from time-control (n = 19) or untreated animals (n = 7). Tissues were analyzed for COX-1 and COX-2 mRNA and protein using RNase protection assay and immunoblot analysis, respectively. Ischemia increased COX-2 mRNA by 30 min, and maximal levels were reached at 2 h. Hypoxia or hypercapnia had minimal effects on COX-2 mRNA. COX-2 protein levels were also consistently elevated by 8 h after I/R. Increases in COX-2 mRNA or protein were not influenced by pretreatment with either indomethacin (5 mg/kg iv, n = 5) or nitro-L-arginine methyl ester (15 mg/kg iv, n = 7). COX-1 mRNA levels were low in time controls, and ischemic stress had no significant effect on COX-1 expression. Thus ischemic stress leads to relatively rapid, selective induction of COX-2 in cerebral arteries.
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PMID:Ischemia-reperfusion rapidly increases COX-2 expression in piglet cerebral arteries. 1048 43

The aim of this study was to assess whether cyclooxygenase (COX) inhibitors protect the endothelial function against the deleterious effect of ischemia and reperfusion. Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow, 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619, and the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation to SNP was unaffected in all groups. Pretreatment with 6-MNA, 30 microM, a COX-2 inhibitor with some activity on COX 1, diclofenac, 1 microM (COX-1 and -2), or 1-(7-carboxyheptyl) imidazole, 10 microM [thromboxane (TX) synthase inhibitor] but not indomethacin, 10 microM (COX-1 inhibitor) preserved the vasodilation induced by 5-HT after ischemia. Enzyme immunoassays indicated that all COX inhibitors decreased the concentration of TXB2 and 6-keto-PGF1alpha [stable metabolites of TXA2 and prostacyclin (PGI2), respectively] in coronary effluent during ischemia. Furthermore, indomethacin was the only one to abolish the concentration of PGE2 during ischemia and early reperfusion. No clear trend on ventricular postischemic recovery could be observed between treated and untreated groups under our experimental protocols. These data suggest that, under our conditions, 6-MNA, diclofenac, and 1-7-CHI, but not indomethacin, protect the endothelial function via a reduction in TX concentration. Disparities between COX inhibitors may be due to the complete abolition of PGE2 concentration during ischemia and reperfusion in the indomethacin group.
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PMID:Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. 1054 94

Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia. Because overactivation of N-methyl-D-aspartate (NMDA) receptors has been implicated in the cell loss associated with ischemia, we characterized the expression of the COX isozymes in murine mixed cortical cell cultures and used isozyme-selective inhibitors to determine their relative contribution to NMDA receptor-stimulated prostaglandin (PG) production and excitotoxic neuronal cell death. Immunocytochemical analysis of mixed cortical cell cultures revealed that COX-2 expression was restricted to neurons, whereas COX-1 was expressed in both neurons and astrocytes. Brief exposure to NMDA (5 min; 100 microM) elicited a time-dependent accumulation of PGs in the culture medium that preceded neuronal cell death and correlated with the induction of COX-2 mRNA. COX-1 expression remained unchanged. Flurbiprofen, a nonselective COX-1/COX-2 inhibitor, blocked NMDA-stimulated PG production and attenuated neuronal death in a concentration-dependent manner. Similar results were obtained with the specific COX-2 inhibitor NS-398 (10-30 microM) but not with the selective COX-1 inhibitor valeryl salicylate (10-300 microM). Inhibition of total constitutive COX activity with aspirin (100 microM, 1.5 h) before NMDA exposure did not prevent subsequent NMDA-mediated neuronal cell death. However, neuronal injury in aspirin-pretreated cultures was attenuated by flurbiprofen administration after NMDA exposure. Finally, the protection afforded by COX-2 inhibition was specific for NMDA because neither flurbiprofen nor NS-398 protected neurons against kainate-mediated neurotoxicity. Together, these results support the conclusion that newly synthesized COX-2 protein contributes to NMDA-induced neuronal injury.
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PMID:Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. 1077 11


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