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)

The metabolism of lipids in the ischemic liver has been examined in the attempt to define the cause of the previously described loss of phospholipid and to determine whether additional alterations occur that may be related to the disturbances in membrane function. With 3 hr of ischemia, 30% of the cellular phospholipid was lost when measured either as phosphate in a lipid extract of the whole liver or as fatty acyl esters after separation by thin-layer chromatography of the major lipid classes in the same extracts. All phospholipid species were equally affected, and there was no accumulation of lysophospholipids. The loss of phospholipid acyl chains was not accompanied by an increased number of acyl esters as mono-, di-, or triglycerides. There was no increase in the size of the free fatty acid pool, and the content of long chain acyl CoA esters decreased by 50%. The acyl chain composition of the free fatty acid and neutral lipid pools changed, however, to resemble more closely that of the phospholipids. There was no change in the fatty acid composition of the phospholipids. The incorporation of intraportally injected [3H]arachidonic acid into total phospholipids was decreased upon reperfusion of liver that had been ischemic for only 20 min. These data are consistent with a loss of fatty acyl chains from the phospholipids into the free fatty acid pool. A few of these chains are incorporated into neutral lipids, but most are lost from the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in the metabolism of lipids in ischemia of the liver and kidney. 403 51

The most important biochemical derangements in ischemic myocardium are the decrease of energy rich phosphates (ATP and phosphocreatine) and intracellular acidosis, both of which contribute to a rapid loss of the contractile function. How and to which extent the alterations of carbohydrate and lipid metabolism are involved in these derangements is briefly discussed. In conditions of oxygen restriction the synchronism between the cytosolic and mitochondrial phase of carbohydrate metabolism is disrupted and beta-oxidation of long chain fatty acids is prevented. Consequently less ATP and more lactate is produced and fatty acids accumulate together with their activation products, acyl CoA in particular. In ischemia free carnitine is also decreased and the carnitine dependent functions (acyl transfer across mitochondrial membrane and pyruvate and alpha ketoglutarate dehydrogenase stimulation) impaired. The meaning of the altered carnitine dependent functions is considered together with the possible (demonstrated and supposed) metabolic effects of carnitine administration in cardiac ischemia.
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PMID:Biochemical derangements in ischemic myocardium: the role of carnitine. 624 Apr 23

Calcium entry into cardiac cells is believed to be controlled by transmembrane-voltage dependent, protein regulated "channels." The sarcoplasmic reticulum participates in the regulation of cytosolic calcium by ATP dependent Ca2+ sequestration during diastole, and by action potential stimulated calcium release. Massive calcium overloading occurs during reperfusion following myocardial ischemia. Calcium overloading activates phospholipases, which may activate another mechanism involved in lethal cellular injury, that is, the accumulation of long chain fatty acids and their derivatives. These compounds are soluble amphiphiles, and once liberated, they may insert into biological membranes and change membrane composition, physiology, and response to ions and drugs. Sarcoplasmic reticulum vesicles were used as an in vitro model to study the effects of palmitic acid, oleic acid, and palmitylcarnitine on the ability of this membrane system to sequester calcium within the vesicles. In the absence of phosphate, palmitic acid enhanced the ability of the vesicles to sequester calcium. Oleic acid and palmitylcarnitine inhibited calcium sequestration. In the presence of phosphate palmitic acid also inhibited the sequestration of calcium by sarcoplasmic reticulum, although not as severely as oleic acid and palmitylcarnitine. These results suggest that the disturbances in cellular calcium homeostasis following ischemia may be due, in part, to the incorporation of accumulated long chain fatty acids into membranes.
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PMID:The possible role of endogenous amphiphiles in the membrane abnormalities of ischemic and reperfused myocardium. 668 Jun 16

The effects of ischemia on in vivo fatty acid metabolism in fetal lung were studied using rabbit fetuses of 25 to 28 gestational age. Ischemia was produced by inflating the aortic balloon thereby reducing the uterine blood flow. Ischemic insult resulted significant increase in lactate/pyruvate and NADH/NAD ratios and decrease in ATP/ADP ratio in fetal lung. Levels of CoA, acetyl CoA, carnitine and acetyl carnitine decreased while those of long chain acyl CoA and long chain acyl carnitine enhanced. Tissue content of these metabolites returned to normal after 2 hr stabilization following 20 min of ischemic insult. Ischemia also caused small increase in lipogenesis and neutral lipid content of fetal lungs. Our results thus suggest that beta-oxidation in fetal lung is inhibited and becomes rate-limiting for fatty acid oxidation during ischemia. Sudden occurrence of hypoxia or ischemia in the fetus is a typical challenge for the obstetricians. The patients occasionally suffer from neurological injury following cerebral hypoxemia. The hypoxic insult may also affect the respiratory activity significantly. For example, acute alveolar hypoxia causes pulmonary vasoconstriction by damaging pulmonary vascular smooth muscle (1) and results in reduction of fatty acid oxidation by limiting the ATP supply required for metabolic processes (2). Hypoxia has also been shown to decrease the rate of palmitate incorporation into phospholipids (3), inhibit rate of fatty acid synthesis (3) and depress rate of incorporation of fatty acid and phosphatidic acid into lipids (4). Despite the fact that fatty acids represent a major substrate for energy metabolism in lung, no work has been done on the fatty acid metabolism in fetal lung. The present study was designed to determine the fate of fatty acid oxidation in fetal lung during ischemic challenge. The levels of acyl CoA and acylcarnitine intermediates were also measured in order to determine the rate-controlling steps of fatty acid metabolism in the fetal lung.
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PMID:Effect of ischemia on fatty acid metabolism in fetal lung. 688 85

Interest in the potential cardiovascular benefits of omega-3 long chain polyunsaturated fatty acids has been largely focused on possible antiatherothrombotic effects. In addition, however, definitive antiarrhythmic effects of these dietary omega-3 fatty acids have been reported by Charnock & McLennan. Our studies commenced with the observation that two of these fatty acids, eicosapentaenoic (C20:5n-3, EPA) and docosahexaenoic acid (C22:6n-3, DHA) prevented contracture and fibrillation of isolated neonatal cardiac myocytes when exposed to toxic levels of ouabain (0.1 mM). This protection was associated with prevention of excessively high intracellular calcium concentrations in the myocyte. Further, it was shown that these fatty acids modulate calcium currents through L-type calcium channels and that the effect occurs within a few minutes of adding EPA or DHA to the medium perfusing the cultured cardiac myocytes. Infusing an emulsion of the omega-3 fatty acids intravenously just prior to compression of a coronary artery in a conscious, prepared dog will prevent the expected subsequent ischemia-induced ventricular fibrillation.
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PMID:Omega-3 fatty acids and prevention of ventricular fibrillation. 778 57

Microsomal fractions of cerebral cortices of 15-day-old rabbits were used to study the 1-alkyl-sn-glycero-3-phosphate (AGP) acetyltransferase that generates 1-alkyl-2-acetyl-sn-glycero-3-phosphate in the de novo path of platelet-activating factor synthesis. The AGP acetyltransferase activity was inhibited by small concentrations of medium-long chain fatty acyl-CoA thioesters. In contrast, the AGP acyltransferase used oleoyl-CoA as substrate and was not inhibited by the presence of acetyl-CoA in high molar excess. The inhibition of AGP acetyltransferase was seen at concentrations of oleoyl-CoA as low as 0.5 microM using 12.5 microM AGP and 200 microM acetyl-CoA. The inhibition by oleoyl-CoA was noncompetitive for the acetyl-CoA substrate. However, there was evidence that the oleoyl-CoA was competing with AGP in the acetyltransferase reaction, as the inhibition was lessened by increasing the AGP substrate concentration. Several acyl-CoA thioesters were effective as inhibitors of the AGP acetyltransferase, including oleoyl-, palmitoyl-, lauroyl-, and octanoyl-CoA. Propionyl- and butyryl-CoA were less effective as inhibitors, and propionyl-CoA was found to be a competitive inhibitor for acetyl-CoA. We have noted earlier that MgATP is an effective inhibitor of the AGP acetyltransferase and here we show that the inhibition by oleoyl-CoA can be increased by the presence of 0.1 mM MgATP. In brain ischemia, a decline in ATP levels would likely lead to a corresponding fall in acyl-CoA concentrations, thereby relieving the inhibition of AGP acetyltransferase and permitting the flow of AGP into the de novo pathway of platelet-activating factor synthesis.
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PMID:Fatty acyl-CoA inhibits 1-alkyl-sn-glycero-3-phosphate acetyltransferase in microsomes of immature rabbit cerebral cortex: control of the first committed step in the de novo pathway of platelet-activating factor synthesis. 779 33

Although accounting for 2% of body weight, brain has one of the greatest metabolic rates compared with other organs and systems. The energy metabolic consum is expended mainly in the maintenance of ionic gradient, essential to neuronal activity. Brain receives energy substrates from circulation, with interference of blood brain barrier (BBB). Glucose is the main substrate and has a metabolic rate so high as 150 g/day (0.7 mM/G/min). At cellular level, metabolism of glucose seems to be controlled by phosphofructokynase. If the cellular level were high enough, manose and other products like fructose 1,6 biphosphate, pyruvate, lactate and acetate can be used in the place of glucose. Lactate, when oxyded, consums at least 21% of the cerebral needs of O2. In ischemia and inflammatory infections, brain tissue produces lactate instead of use it. Ketone bodies reduce cerebral needs of glucose; in view of the disturbances that occur in cerebral production of succinyl CoA and guanosine 3 phosphate (GTP), they must be considered as complementary substrate but not as an alternative one. Although they can be metabolized, there are no evidences that brain could produce energy from systemic free fatty acids, even when hypoglicemia is present. Ethanol and glycerol are considered only at experimental level. Brain uptake of aminoacids occur better for long chain aminoacids, specially valine. The aminoacids that are synthetised in the brain (aspartate, gluconate and alanine) show the lower absortion rates. All aminoacids should be oxided to CO2 and H2O. Even when glucose consum is reduced to 30%, aminoacid accounts for only 10% of the energetic expenditure of the brain. To maintain cerebral glucose and oxygen supply to the brain, blood flow must be at least 800 ml/min. The regulation of supply and consumption of energy substrate by the brain is changed in few situations. Among them, are included the oxidation of lactate immediately before milk diet early in development and utilization of ketone bodies at the beginning of lactation. This review includes a brief discussion about the relevance of glucose as the main energy substrate for cerebral tissue in different ages and ischemia or hypoxia.
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PMID:[Control of supply and use of energy substrates in the encephalon]. 858 33

A study of substrate selection in the isolated heart was made using 13C NMR isotopomer analysis, a method that unequivocally identifies relative substrate utilization. This technique has several advantages over conventional approaches used to study this problem. It detects the labeling of metabolic end-products present in tissue, as opposed to more indirect methods such as measurement of respiratory quotient, arteriovenous differences, or specific activity changes in the added substrate. It also has advantages over methods such as 14CO2 release, which may involve dilution of label with unlabeled pools before CO2 release. Furthermore, it can measure the relative oxidation of up to four substrates in a single experiment, which other labeling techniques cannot conveniently achieve. Substrate selection was considered in light of its effects on myocardial efficiency and recovery from ischemia. A mixture of four substrates (acetoacetate, glucose, lactate, and a mixture of long chain fatty acids), present at physiological concentration (0.17, 5.5, 1.2, and 0.35 mM, respectively), was examined. This is the first use of such a mixture in the study of substrate selection in an isolated organ preparation. At these concentrations, it was found that fatty acids supplied the majority of the acetyl-CoA (49%), and a substantial contribution was also provided by acetoacetate (23%). This suggests that the ketone bodies are a more important substrate than generally considered. Indeed, normalizing the relative utilizations on the basis of acetyl-CoA equivalents, ketone bodies were by far the preferred substrate. The relative lactate oxidation was only 15%, and glucose oxidation could not be detected. No change in utilization was detected after 15 min of ischemia followed by 40 min of reperfusion. The change in substrate selection with afterload was examined, to mimic the stress-related changes in workload found with ischemia. Only minor changes were found. Substrate selection from the same group of substrates, but employing concentrations observed during starvation, was also assessed. This represents the state during which most clinical treatments and evaluations are performed. In this case, acetoacetate was the most used substrate (78%), with small and equal contributions from fatty acids and endogenous substrates; the oxidation of lactate was suppressed.
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PMID:Substrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentration. 858 60

Long-chain acylcarnitines accumulate during myocardial ischemia and contribute to membrane dysfunction in ischemic zones. On the basis of the 3-fold selectivity for saturated fatty acid accumulation during myocardial ischemia, it was implicitly assumed that saturated long chain acylcarnitine molecular species predominantly accumulated in ischemic myocardium. By exploiting the analytical power of electrospray ionization mass spectroscopy, we now report that unsaturated acylcarnitines are the predominant molecular species of acylcarnitine which accumulate during myocardial ischemia (rank order: octadecadienoyl carnitine > octadecanoyl carnitine > hexadecanoyl carnitine > octadecanoyl carnitine). The aliphatic chain distribution of myocardial acylcarnitine molecular species identified by electrospray ionization mass spectroscopy was independently substantiated by sequential HPLC purification and capillary gas chromatography. Detailed analysis of the individual molecular species of long-chain acylcarnitine demonstrated that fatty acyl chain elongation was prominent in ischemic myocardium (e.g., following 20 min of ischemia, greater than 15% of the accumulated acylcarnitines consisted of 20-carbon unsaturated molecular species). Chain-elongated lipids were essentially confined to the long chain acylcarnitine pool since [9,10-3H]octadec-9'-enoic acid was converted to [3H]eicosenoyl carnitine (12% of the radiolabeled acylcarnitine pool) in ischemic hearts without substantive amounts of [3H]eicosenoyl residues in the fatty acid, triglyceride, and phospholipid pools. Collectively, these results demonstrate the preponderance of unsaturated acylcarnitines in ischemic myocardium and document the metabolic compartmentation of downstream products of fatty acyl chain elongation in the acylcarnitine pool during ischemia.
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PMID:Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. 867 92

In this study, ischemia and oxidative stress-inducible gene expression in heart was examined by subtractive hybridization technique. Total RNA was isolated from ventricular muscle fragments of normal and oxidative stress-induced hearts. Poly (A)+ RNA was purified followed by the construction of a plasmid cDNA library. This was followed by the subtractive screening of oxidative stress-induced cDNA library. The positive colonies were amplified and the plasmid isolated. An aliquot was subjected to restriction cutting with Bam H1 and EcoR1; the fragments corresponding to cDNA insert were separated by electrophoresis, radiolabeled by random-primed DNA synthesis, and used as probes in standard Northern blotting experiments. An aliquot containing the plasmid from the confirmed positives was then subjected to bidirectional partial DNA sequencing (using M13 and T7/T3 alpha primers) by the chain-extension/chain termination method. These sequences were subjected to a computerized search for homologies against all sequences in the updated worldwide Gen Bank and EMBL sequence databases followed by restriction mapping and reading frame identification. Out of 24 putative positive colonies screened, one clone was matched with > 97% homology with FAT gene that has been implicated in binding or transport of long chain fatty acids. cDNA probe synthesized from this clone identified two major transcripts of 4.8 and 2.9 kb. Additional experiments were then performed where isolated perfused rat hearts were subjected to the following treatments: (1) 5 min ischemia; (2) 10 min ischemia; (3) 20 min ischemia; (4) 5 min ischemia followed by 10 min reperfusion (ischemic preconditioning); and (5) 5 min ischemia followed by 10 min reperfusion, repeated four times (4 x preconditioning). RNAs were extracted from these hearts and hybridized with the FAT cDNA probe. The results indicated the FAT gene was induced by oxidative stress, ischemic preconditioning, but not by ischemia.
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PMID:Molecular cloning, sequencing and expression analysis of a fatty acid transport gene in rat heart induced by ischemic preconditioning and oxidative stress. 890 79


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