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)

Lysophosphatidylcholine (LPC) increases extracellularly during ischemia in vivo in both animals and man as judged by measurements from venous effluents, but more recent studies have shown little or no increase in buffer-perfused, isolated heart preparations. The appearance of LPC in blood and lymph in animals and in venous effluents in man in response to ischemia suggests a vascular site for the production of LPC. The present study was performed to assess whether thrombin could stimulate phospholipase A2 in endothelial cells and whether this would evoke an increase in and release of LPC. Endothelial cells were disassociated from canine aortas by incubating with 0.1% collagenase for 20 min. Cells were plated and allowed to grow to confluence. Measurement of LPC was performed using Bligh and Dyer extraction of lipids, high performance liquid chromatography separation, and quantification of LPC using a recently developed radiometric assay employing [3H]acetic anhydride. Incubation of endothelial cells with thrombin (0.05 unit/ml) resulted in a 2.5-fold increase in LPC to 2.3 +/- 0.1 nmol/mg of protein at 2 min (p < 0.01) and returned to control levels within 20 min. The increase in LPC induced by thrombin exhibited a concentration-dependent response with an ED50 = 0.04 unit/ml. A concentration-dependent increase in LPC was also elicited by stimulation with the peptide portion of the thrombin receptor's tethered ligand SFLLRNPNDKYEPF with an ED50 = 8 microM. The LPC produced was rapidly and completely released into the surrounding media. Hirudin completely blocked the thrombin-induced increase in LPC. Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (0.1 microM), which rapidly inactivates thrombin's proteolytic activity in situ without impairing binding, or phenyl-prolyl-arginyl-chloromethyl ketone (PPACK, 5 nM), which inactivates thrombin due to chemical alteration of the proteolytic site, each prevented the increase in LPC in response to thrombin. Stimulation of protein kinase C with phorbol 12-myristate-13-acetate (PMA, 1 microM) enhanced the response to thrombin. In contrast, staurosporine (100 nM), H7 (15 microM), or chronic treatment with PMA for 20 h to down-regulate protein kinase C completely prevented the increase in LPC in response to thrombin. Thus, thrombin stimulation of endothelial cells in vivo during ischemia may be a primary mechanism contributing to the marked increase in LPC extracellularly during ischemia.
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PMID:Thrombin-induced release of lysophosphatidylcholine from endothelial cells. 839 49

Phospholipid-hydrolyzing activities were examined in rat hearts with ischemia induced by occlusion of the left main coronary artery. When homogenates of ischemic heart were incubated in vitro at 37 degrees C, a significant amount of phosphatidylethanolamine (PE) was degraded, whereas the contents of other phospholipids did not change significantly. During the incubation, a stoichiometrical amount of lysoPE was concomitantly formed. The lysoPE formed had mainly saturated fatty acids and its composition resembled that of fatty acids detected at the sn-1 position in the glycerol backbone of heart PE. No appreciable PE degradation was observed in homogenates prepared from nonischemic rat heart. No difference in phospholipase activities was found between ischemic and nonischemic heart homogenates when exogenous radioactive phospholipids were used as substrates. Rabbit anti-rat 14-kDa type II phospholipase A2 antibody suppressed the degradation of PE observed in ischemic heart homogenates. These findings indicate that the type II phospholipase A2 activity may be involved in the breakdown of endogenous PE in ischemic heart homogenates.
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PMID:Preferential hydrolysis of phosphatidylethanolamine in rat ischemic heart homogenates during in vitro incubation. 840 72

In a recent study, reperfusion mucosal injury was demonstrated in a rat model of total ischemia if venous congestion was avoided. The aims were to examine the possibility of reperfusion damage in a canine model involving 2 hours of complete segmental ischemia and to investigate the effects of antioxidant therapy or pretreatment with nonspecific phospholipase A2 inhibitors on postocclusive mucosal changes. Tissue samples were evaluated histologically in a blind manner, according to a 0 to V grade scale. The degree of mucosal damage was statistically significantly increased during the 30-minute reperfusion period. Similarly, 2 hours of total ischemia followed by 30 minutes of reperfusion produced significantly more tissue lesions than did 2 1/2 hours of ischemia without reperfusion. Oral allopurinol pretreatment supplemented by an intravenous dose, or oral allopurinol in combination with a superoxide radical scavenger, resulted in a significant amelioration of postischemic histologic changes. Pretreatment with a nonspecific phospholipase A2 inhibitor (methylprednisolone, dexamethasone, or quinacrine) was ineffective in diminishing the reperfusion injury in either case. The results suggest that reperfusion injury may develop even after complete intestinal ischemia, and this damage can be attenuated by inhibiting the capacity of xanthine oxidase to generate reactive oxygen intermediates.
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PMID:Reperfusion mucosal damage after complete intestinal ischemia in the dog: the effects of antioxidant and phospholipase A2 inhibitor therapy. 843 Mar 67

A novel active-site directed specific inhibitor of phospholipase A2 (PLA2), 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33), administered endotracheally co-dispersed in liposomes, significantly reduced the formation of thiobarbituric acid reactive substances (TBARS) in isolated rat lungs subjected to ischemia-reperfusion. Elevated conjugated dienes were unaffected. This contrasts with the effects of the cyclo-/lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA), which decreased formation of both TBARS and conjugated dienes (CD). The effects of MJ33 plus ETYA were additive for TBARS but results for CD were similar to ETYA alone. A similar dissociation of inhibition of TBARS and CD formation by MJ33 was observed with t-butyl hydroperoxide induced lipid peroxidation of isolated lung microsomes. Assay of lung homogenate with phosphatidylcholine as substrate showed that MJ33 selectively inhibited the Ca(2+)-independent acidic PLA2. MJ33 had no effect on thromboxane B2 release by the isolated lung, indicating the effects of acidic PLA2 inhibition do not involve the arachidonate cascade. MJ33 also partially prevented lung edema and lactate dehydrogenase release associated with ischemia-reperfusion. The observations show that this PLA2 inhibitor can be delivered to oxidant-sensitive lung sites by its co-dispersal in liposomes, and that oxidant-induced lipid peroxidation in this model of lung injury occurs in a complex lipid prior to PLA2 activity.
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PMID:A phospholipase A2 inhibitor decreases generation of thiobarbituric acid reactive substance during lung ischemia-reperfusion. 846 33

In ischemic organs, arachidonic acid (AA) metabolites and mostly prostaglandins (PGs) have been found to be released in high amounts. The mechanism for this AA metabolism activation and its physiological implications are not clear. Because endothelial cells are an important source of PGs and because they seem to be very rapidly affected by ischemia, we developed an in vitro model where human endothelial cells were submitted to hypoxia. An important specific activation of phospholipase A2 was observed during hypoxia, which was concomitant with a rise in cytosolic calcium concentration. Endothelial cells synthetize in normal conditions as a mean 1.42, 1.00, 7.69, and 26.92 ng/mg proteins of, respectively, PGE2, PGD2, PGF2 alpha, PGI2. An important increase of about five- to ninefold in the synthesis of the four PGs was observed during hypoxia, which followed the same kinetics as the PLA2 activation. This increase in PG synthesis was sensitive to cyclooxygenase inhibitors. During reoxygenation, PG synthesis decreased back to the basal level of resting cells, suggesting that cells were able to recover their homeostasis after hypoxia. These observations indicate that endothelial cells exposed to oxygen deprivation are a major source of PGs and could contribute to the high amounts of PG released in vivo in ischemic organs.
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PMID:Stimulation of prostaglandin synthesis by human endothelial cells exposed to hypoxia. 847 19

Despite the known effectiveness of anti-inflammatory therapy in reducing reperfusion injury, no studies to date involve the use of anti-inflammatory therapy in reducing ischemia-reperfusion injury in fasciocutaneous flaps. Dexamethasone (a phospholipase A2 inhibitor) and specific cyclooxygenase and lipoxygenase inhibitors (indomethacin and BW755C) were administered to rats with ischemic island groin (fasciocutaneous) flaps. Significant improvement in ischemic flap survival was found with dexamethasone and BW755C. The mode of action of dexamethasone was not specifically investigated in our study; however, it may suppress neutrophil function and reduce ischemia-reperfusion injury in its shared ability with BW755C to reduce the formation of leukotrienes. Dexamethasone could be applied in the clinical setting to reduce ischemic flap loss by attenuating the systemic inflammatory response to reperfused ischemic-damaged tissue.
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PMID:Reducing ischemia-reperfusion injury in rat island groin flaps by dexamethasone and BW755C. 852 85

Membrane lipid-derived second messengers are generated by phospholipase A2 (PLA2) during synaptic activity. Overstimulation of this enzyme during neurotrauma results in the accumulation of bioactive metabolites such as arachidonic acid, oxygenated derivatives of arachidonic acid, and platelet-activating factor (PAF). Several of these bioactive lipids participate in cell damage, cell death, or repair-regenerative neural plasticity. Neurotransmitters may activate PLA2 directly when linked to receptors coupled to G proteins and/or indirectly as calcium influx or mobilization from intracellular stores is stimulated. The release of arachidonic acid and its subsequent metabolism to prostaglandins are early responses linked to neuronal signal transduction. Free arachidonic acid may interact with membrane proteins, i.e., receptors, ion channels, and enzymes, modifying their activity. It can also be acted upon by prostaglandin synthase isoenzymes (the constitutive prostaglandin synthase PGS-1 or the inducible PGS-2) and by lipoxygenases, with the resulting formation of different prostaglandins and leukotrienes. Glutamatergic synaptic activity and activation of postsynaptic NMDA receptors are examples of neuronal activity, linked to memory and learning processes, which activate PLA2 with the consequent release of arachidonic acid and platelet-activating factor (PAF), another lipid mediator. Both mediators may exert presynaptic and postsynaptic effects contributing to long-lasting changes in glutamate synaptic efficacy or long-term potentiation (LTP), PAF, a potential retrograde messenger in LTP, stimulates glutamate release. The PAF antagonist BN 52021 competes for receptors in presynaptic membranes and blocks this effect. PAF may also be involved in plasticity responses because PAF leads to the expression of early response genes and subsequent gene cascades. The PAF antagonist BN 50730, selective for PAF intracellular binding, blocks PAF-mediated induction of gene expression. A consequence of neural injury induced by ischemia, trauma, or seizures is an increased release of neurotransmitters, that in turn generates an overproduction of second messengers. Glutamate, a key player in excitotoxic neuronal damage, triggers increased permeation of calcium mediated by NMDA receptors and activation of PLA2 in postsynaptic neurons. NMDA receptor antagonists reduce the accumulation of free fatty acids and elicit neuroprotection in ischemic damage. Increased production of free arachidonic acid and PAF converges to exacerbate glutamate-mediated neurotransmission. These neurotoxic actions may be brought about by arachidonic acid-induced potentiation of NMDA receptor activity and decreased glutamate reuptake. On the other hand, PAF stimulates the further release of glutamate at presynaptic endings. The neuroprotective effects of the PAF antagonist BN 52021 in ischemia-reperfusion are due, at least in part, to an inhibition of presynaptic glutamate release. PAF also induces expression of the inducible prostaglandin synthase gene, and PAF antagonists selective for the intracellular sites inhibit this effect. The PAF antagonist also inhibits the enhanced abundance, due to vasogenic cerebral edema and ischemia-reperfusion damage, of inducible prostaglandin synthase mRNA in vivo. Therefore, PAF, an injury-generated mediator, may favor the formation of other cell injury and inflammation mediators by turning on the expression of the gene that encodes prostaglandin synthase.
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PMID:Mediators of injury in neurotrauma: intracellular signal transduction and gene expression. 859 8

Our previous in vivo studies have implicated phospholipase A2 activation and platelet-activating factor (PAF) production as an important mediator of neutrophil (PMN) priming after mesenteric ischemia/reperfusion. Furthermore, our in vitro studies demonstrate that PAF priming of PMN enhances PMN respiratory burst and increases PMN adherence to human umbilical vein endothelial cell cultures (HUVEC). Others have shown that cytokine stimulated HUVEC can activate quiescent PMNs to provoke endothelial cell (EC) monolayer disruption via EC detachment by a noncytolytic PMN protease mechanism. Hypoxia and reoxygenation (H/R) of HUVEC can also directly stimulate PAF production. Consequently, we hypothesized that HUVEC H/R can activate quiescent PMNs to disrupt the EC monolayer (detachment) through a PAF mediated mechanism. HUVEC were labeled with 51 chromium (51Cr) and subjected to 45 min hypoxia (95% N2/5% CO2). PMNs freshly isolated by Percoll gradient centrifugation were added to HUVEC and reoxygenated for 120 min. Additionally, H/R HUVEC with PMN pretreated with WEB2170 (a PAF receptor antagonist) was compared to control (non-H/R HUVEC incubated with PMNs). Wells were washed at end incubation, and adherent ECs counted. Detachment = [total counts - sample counts]/total counts X 100. H/R HUVEC plus PMN provoked a 29.3 +/- 1.6% detachment of EC compared to 9.3 +/- 2.9% detachment in control (non-H/R HUVEC with PMNs). In contrast, H/R HUVEC with PMNs preincubated with WEB2170 had 9.9 +/- 3.8% detachment of EC. In summary, HUVEC H/R activated quiescent PMNs to disrupt an EC monolayer (detachment) via a PAF mechanism.
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PMID:Hypoxia/reoxygenation of human endothelium activates PMNs to detach endothelial cells via a PAF mechanism. 865 25

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.
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PMID:CDP-choline: pharmacological and clinical review. 870 78

Cerebral insult is associated with a rapid increase in free fatty acids (FFA) and arachidonic acid release has been linked to the increase in eicosanoid biosynthesis. In transient focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion, there is an inverse relationship between the increase in FFA and the decrease in ATP, both during the ischemia period and at later time periods after reperfusion. In this study, the focal cerebral ischemia model was used to examine incorporation of [14C]arachidonic acid into the glycerolipids in rat MCA cortex at different reperfusion times after a 60 min ischemia. The label was injected intracerebrally into left and right MCA cortex 1 hr prior to decapitation. Labeled arachidonic acid was incorporated into phosphatidylcholine, phosphatidylethanolamine and neutral glycerides. With increasing time (4-16 hr) after a 60 min ischemia, an inhibition of labeled arachidonate uptake could be found in the right ischemic MCA cortex, whereas the distribution of radioactivity among the major phospholipids was not altered. When compared to labeled PC, there was a 3-4 fold increase in incorporation of label into phosphatidic acid and triacylglycerols (TG) in the right MCA cortex, suggesting of an increase in de novo biosynthesis of TG. In an in vitro assay system, synaptosomal membranes isolated from MCA cortex 8 and 16 hr after a 60 min ischemia showed a significant decrease in arachidonoyl transfer to lysophospholipids, due mainly to a decrease in lysophospholipid:acylCoA acyltransferase activity. Assay of phospholipase A2 activity with both syaptosomes and cytosol, however, did not show differences between left and right MCA cortex or with time after reperfusion. These results suggest that besides ATP availability, the decrease in acyltransferase activity may also contribute to the increase in FFA in cerebral ischemia-reperfusion.
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PMID:Regulation of FFA by the acyltransferase pathway in focal cerebral ischemia-reperfusion. 878 13


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