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)

Phospholipid metabolism is altered during ischemia and post-ischemic reperfusion. Past studies demonstrating elevated myocardial free fatty acid and lysophospholipid content infer accelerated phospholipid degradation involving phospholipase A activity. Recently, ischemic and post-ischemic reperfusion (reperfusion) have been shown to affect levels of phosphoinositide (PPI) degradation products. Considering the role of PPI turnover in regulation of cellular calcium homeostasis, our laboratory and others have suggested that alteration in the metabolism of the inositol phospholipids could play a role in the development of ischemia-induced calcium overload injury. Using an isolated rat heart model (Langendorff perfusion), this study examines the effect of global ischemia and reperfusion on ventricular phosphoinositide-specific phospholipase C (PLC) activity and PLA2 activity. The primary purpose was to determine if ischemia and reperfusion-induced changes in PLC activity could explain previously observed changes in PPI degradation products, and whether PLC and PLA2 activities were similarly or differentially altered by ischemia and reperfusion. PLC and PLA2 activities were measured in cytosolic and total membrane fractions from control (perfused), ischemic (5, 10, 30, and 60 min), and post-ischemic reperfused ventricular tissue. Phospholipase activity was determined under optimal in vitro conditions using exogenous radiolabeled substrates. Alterations in membrane-associated PPI-PLC activity correlated with reported ischemia and reperfusion-induced changes in ventricular content of PPI metabolites. Membrane PLC activity increased slightly at 5 min of ischemia, decreased significantly at 10 min of ischemia, and continued to decrease with longer duration of ischemia (73% of control after 60 min). Cytosolic PPI-PLC activity was decreased at 5 min, and then significantly increased by longer durations of ischemia, while cytosolic PLA2 activity was reduced at all time points. Pretreatment with muscarinic, alpha 1-adrenergic, beta-adrenergic, and adenosine receptor blockers did not alter ischemia-elicited changes in PLC activity. Reperfusion caused a 140% to 200% rise in the activities of all phospholipases in all fractions after 40 min of ischemia, but not after 10 min of ischemia. Results suggest 1) ischemia and reperfusion-elicited alterations in membrane-associated PPI-PLC activity can explain previously observed changes in phosphoinositide turnover metabolites, 2) cytosolic and membrane-associated PPI-PLC and PLA2 activities are not uniformly affected by ischemia, 3) reperfusion following ischemia of sufficient duration initiates uniform activation of PIP2-PLC and PLA2, and 4) because ischemia and reperfusion-induced changes in phospholipase activity can be detected under optimal in vitro assay conditions (removed from the in vivo ischemic microenvironment), it is likely that the enzymes themselves have been altered.
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PMID:Changes in phosphoinositide-specific phospholipase C and phospholipase A2 activity in ischemic and reperfused rat heart. 159 Jul 34

While it has been postulated that lyso-PAF and PAF might contribute to structural and functional damage in myocardial ischaemia, there has been no clear evidence for the accumulation of these bioactive compounds in ischaemic myocardium. In open chest, anaesthetised dogs, the proximal left anterior descending coronary artery was ligated and myocardial samples from the central ischaemic and normal areas assayed for lyso-PAF, free arachidonic acid and PLA2 activity. Ischaemic myocardium contained 50 +/- 29% (SD) more lyso-PAF than non-ischaemic myocardium after 20 min ischemia (P less than 0.002; N = 8) and 53 +/- 39% more after 60 min (P less than 0.01; N = 8) but there was no difference after 10 min (N = 8). Free arachidonic acid significantly increased in ischaemic myocardium after 60 min (122 +/- 136%; P less than 0.05) while no increase in PLA2 activity was found in-vitro. Since lyso-phospholipids themselves damage cell membranes and, additionally, lyso-PAF is the precursor of PAF which has potent effects on platelets, leukocytes and small vessels, the increase in lyso-PAF in ischaemic myocardium could contribute to myocardial damage.
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PMID:The lyso-precursor of platelet-activating factor (lyso-PAF) in ischaemic myocardium. 176 76

Acute renal failure induced by the administration of gentamicin (GM) was studied enzymochemically in comparison with that in rats with tubular disorder resulting from postischemic reperfusion. Renal ischemia was caused by clamping the renal artery for 30 minutes to create complete ischemia and reflow. The activities of renal tissue glutathione peroxidase (GSH-Px) and the values to the renal contents of glutathione (GSH) and malondialdehyde (MDA) were measured in each sample. In order to confirm whether GSH plays an important role in the intrinsic anti-oxidant system in this model, buthionine sulfoximine (BSO), which is a gamma-glutamylcysteine synthetase inhibitor, was administered intraperitoneally to decrease the renal GSH content before the procedure in renal ischemia. On the other hand, the GM-induced ARF model was made by injection with GM 100 mg/kg during a period of 5 days. In the GM group, a significant increase in MDA and a reduction in the sphigomyelin (SPH)/phosphatidylcholine (PC) ratio and inactivation of PLA2 were observed. In the kidney tissue obtained 15 min. after reperfusion, the renal content of MDA was elevated markedly in the BSO-preadministered group. A reduction of SPH/PC ratio was also observed in the reperfusion model. PAL2 hydrolyzes the acyl group at the 2-position containing much of the highly unsaturated fatty acids that are easily oxidized. Further, PLA2 is considered to act directly on one of PC or phosphatidylinositol. Phospholipidosis thesauruses, noted in acute renal failure induced by GM, is considered to be caused by reduced liberation of lysosomal intramembranous phospholipid into the cytoplasm and accelerated peroxidation of intramembranous lipid.
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PMID:[Lipid peroxidation and tubular disorder in experimental acute renal failure-enzymochemical study in the rat kidney]. 807 17

Phospholipases A2 comprise a family of enzymes that hydrolyze the acyl bond at the sn-2 position of phospholipids to generate free fatty acids and lysophospholipids. In the central nervous system products of PLA2 regulate neurotransmission. In addition, the lysophospholipids, free fatty acids, eicosanoids, platelet activating factor and reactive oxygen species, generated by enhanced PLA2 activity and arachidonic acid metabolism, may be responsible for many destructive cellular processes in neuronal tissue. There are interactions between glutamate and PLA2 and its products which suggest that PLA2 activity plays an important role in excitotoxic neuronal cell injury associated with ischemia. Our laboratory has demonstrated that multiple forms of Ca(2+)-dependent PLA2 are present in the gerbil brain. These forms differ from previously described forms and from each other. After ischemia and reperfusion, cytosolic, mitochondrial/synaptosomal and microsomal PLA2 enzymatic activities are enhanced. These stable modifications of enzymatic activity cannot be explained by a direct effect of Ca2+ alone and our data suggest that regulatory influences other than Ca2+ may play an important role in PLA2 activation and mediation of cellular injury after an ischemic insult.
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PMID:Phospholipase A2 (PLA2) activity in gerbil brain: characterization of cytosolic and membrane-associated forms and effects of ischemia and reperfusion on enzymatic activity. 835 4

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

Protein tyrosine phosphorylation plays an important role in neuronal function. In this study we have examined the effects of inhibition of tyrosine phosphorylation on the extracellular levels of four neurotransmitter amino acids (aspartate, glutamate, gamma-aminobutyric acid (GABA) and glycine) and of the non-transmitter amino acid phosphoethanolamine during cerebral ischemia and reperfusion in a rat four vessel occlusion model. In comparison with the control group, the tyrosine kinase inhibitor genistein significantly depressed ischemia/reperfusion-evoked efflux of these amino acids, with the exception of GABA, into cerebral cortical superfusates. GABA efflux was non-significantly reduced. These results suggest that tyrosine phosphorylation is involved in the ischemia-evoked efflux of amino acids into the extracellular milieu, likely as a consequence of the phosphorylation of microtubule-associated protein kinase (MAP kinase) and downstream activation of PLA2 in the plasma membrane. Amino acid efflux would occur, in part, as a consequence of the ensuing disruption of plasma membrane integrity and leakage of cytoplasmic constituents along their concentration gradients.
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PMID:Inhibition of tyrosine phosphorylation attenuates amino acid neurotransmitter release from the ischemic/reperfused rat cerebral cortex. 872 72

Fluoride (F) is a widely distributed nephrotoxin with exposure potentially resulting from environmental pollution and from fluorinated anesthetic use (eg, isoflurane). This study sought to characterize some of the subcellular determinants of fluoride cytotoxicity and to determine whether subtoxic F exposure affects tubular cell vulnerability to superimposed ATP depletion and nephrotoxic attack. Human proximal tubular cells (HK-2) were cultured with differing amounts of NaF (0 to 20 mmol/L, overlapping with clinically relevant intrarenal/urinary levels after fluorinated anesthetic use). After completing 24-hour exposures, cell injury was determined (vital dye uptake). Fluoride effects on cell deacylation ([3]H-C20:4 release) and PLA2 activity were also assessed. To determine whether subtoxic F exposure alters tubular cell susceptibility to superimposed injury, cells were exposed to subtoxic NaF doses for 0 to 24 hours and then challenged with simulated ischemia (ATP depletion plus Ca2+ overload) or a clinically relevant nephrotoxic insult (myoglobin exposure). NaF induced dose-dependent cytotoxicity (up to approximately 90% vital dye uptake and increased [3H]C20:4 release). Extracellular Ca2+ chelation (EGTA) and PLA2 inhibitor therapy (aristolochic acid, dibucaine, or mepacrine) each conferred significant protective effects. When subtoxic NaF doses were applied, partial cytosolic PLA2 depletion rapidly developed (approximately 85% within 3 hours, determined on cell extracts). These partially PLA2-depleted cells were markedly resistant to ATP depletion/Ca2+ ionophore injury and to myoglobin-induced attack (approximately 50% decrease in cell death). We conclude that 1) F induces dose-dependent cytotoxicity in cultured human proximal tubular cells, 2) this occurs, in part, via Ca(2+)- and PLA2-dependent mechanism(s), 3) partial cytosolic PLA2 depletion subsequently results, and 4) subtoxic fluoride exposure can acutely increase cell resistance to further attack. Reductions in cytosolic PLA2 activity could potentially contribute to this result.
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PMID:Inorganic fluoride. Divergent effects on human proximal tubular cell viability. 903 86

This study was performed to determine the involvement of type II phospholipase A2 (PLA2-II) in renal injury caused by ischemia and reperfusion. Ischemia and reperfusion significantly elevated levels of blood urea nitrogen and serum creatinine in rats. These increases were significantly reduced by i.v. administration of rabbit IgG F(ab')2 fragments against rat PLA2-II. Increased levels of acid-stable PLA2 activity in the kidney were caused by ischemia and reperfusion, and were suppressed by administration of anti-PLA2-II F(ab')2. Increased levels of myeloperoxidase activity, a marker of neutrophil infiltration, in the kidney were also reduced after anti-PLA2-II F(ab')2 treatment. These results suggest that PLA2-II plays a pivotal role in pathogenesis of ischemia and reperfusion injury through induction of neutrophil infiltration.
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PMID:Antibodies against type II phospholipase A2 prevent renal injury due to ischemia and reperfusion in rats. 987 6

In order to obtain baseline information on the secretory function of normal rat bowel for our work on intestinal graft ischemia, we studied several biochemical parameters in rat Thiry-Vella fistulas (TVF). TVFs were created in 200-g male Lewis rats (n = 11) using the 25-cm segment of jejunum normally used as a graft in our intestinal transplant model. The stomas were matured primarily and the animals were allowed to recover. The TVFs were flushed at 0, 6, and 24 h and then daily for up to 21 days with 12 mL normal saline solution. The effluent was collected and analyzed for total protein (TP), secretory phospholipase A2 (sPLA2), intestinal fatty acid binding protein (I-FABP), lactate dehydrogenase (LDH), and N-acetylglucosamine (NAGA). TP content was 0.12 +/- 0.01 mg/mL up to 48 h, then gradually increased and stabilized at 0.39 +/- 0.05 mg/mL at day 21. By sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), one major protein band was identified in the low-molecular-mass range (15 kD), consistent with I-FABP and sPLA2. Secretory PLA2 levels decreased over the first 4 days to a low of 115 +/- 24.8% hydrolysis/min/fraction, then gradually rose to a plateau at approximately 529.76 +/- 88.36% hydrolysis/min/fraction by day 18. I-FABP levels rose rapidly from 0 ng/mL at 2 h to 900 +/- 250.0 ng/mL at 6 h and approximately 3000 +/- 304.9 ng/mL by day 14. LDH levels at 2 h and 48 h did not differ, with 0.03 +/- 0.004 and 0.03 +/- 0.005 optical density units (OD)/min/mL, respectively. NAGA levels were 0.07 +/- 0.05 OD/h/mL at 2 h and rose to 0.14 +/- 0.04 OD/h/mL at 48 h. These data suggest that after an early equilibration period, biochemical secretion into the lumen of normal rat bowel reaches a state of equilibrium, and therefore appears to reflect the baseline biochemical status of the bowel. Some of these levels are not negligible as one would expect in "normal" bowel. This information should prove extremely helpful as a baseline study of abnormal conditions of the intestine, such as ischemia or rejection.
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PMID:Biochemical alterations in rat Thiry-Vella fistulas. 1080 Oct 46

Docosahexaenoic acid (DHA) accumulates in nerve endings of the brain during development. It is released from the membrane during ischemia and electroconvulsive shock. DHA optimizes neurologic development, it is neuroprotective, and rat adrenopheochromocytoma (PC12) cells have decreased PLA2 activity when DHA is present. To characterize DHA metabolism in PC12 cells, media were supplemented with [3H]DHA or [3H]glycerol. Fractions of nerve growth cone particles (NGC) and cell bodies were prepared and the metabolism of the radiolabeled substrates was determined by thin-layer chromatography. [3H]glycerol incorporation into phospholipids indicated de novo lipid synthesis. [3H]DHA uptake was more rapid in the cell bodies than in the NGC. [3H]DHA first esterified in neutral lipids and later in phospholipids (phosphatidylethanolamine). [3H]glycerol primarily labeled phosphatidylcholine. DHA uptake was compartmentalized between the cell body and the NGC. With metabolism similar to that seen in vivo, PC12 cells are an appropriate model to study DHA in neurons.
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PMID:Uptake and incorporation of docosahexaenoic acid (DHA) into neuronal cell body and neurite/nerve growth cone lipids: evidence of compartmental DHA metabolism in nerve growth factor-differentiated PC12 cells. 1090 34


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