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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although numerous studies have implicated accelerated phospholipid catabolism during myocardial ischemia as an important contributor to ischemic membrane dysfunction, no information is currently available on the subcellular distribution, physical properties, or kinetic characteristics of human myocardial phospholipase A2. In this report, we demonstrate that the overwhelming majority (98%) of total phospholipase A2 activity in human myocardium (obtained from transplant recipients) is calcium independent, plasmalogen selective, and is distributed between the microsomal (60-70% of total activity) and cytosolic (30-40% of total activity) fractions. Both human myocardial microsomal and cytosolic phospholipase A2 enzymes 1) preferentially hydrolyze plasmalogen molecular species containing arachidonic acid at the sn-2 position, 2) are recalcitrant to chemical inactivation by the indole-reactive agent parabromophenacyl bromide, 3) are irreversibly inhibited by covalent modification of an essential thiol residue by 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB), and 4) are exquisitely sensitive to mechanism-based inhibition by (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (bromoenol lactone). In sharp contrast, human mitochondrial phospholipase A2 1) accounts for only a diminutive amount of total myocardial phospholipase A2 activity (1-2%), 2) is augmented by calcium ion, 3) exhibits a higher reaction velocity using phosphatidylcholine in comparison with plasmenylcholine substrate, and 4) is not substantially inhibited by either DTNB or bromoenol lactone. Collectively, these results demonstrate that the majority of phospholipase A2 activity in human myocardium is catalyzed by a novel class of calcium-independent plasmalogen-selective phospholipases A2 and underscore the potential importance of this class of enzymes in mediating membrane dysfunction during myocardial infarction in humans.
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PMID:Identification and characterization of human myocardial phospholipase A2 from transplant recipients suffering from end-stage ischemic heart disease. 153 86

The activity of phospholipase A2 in blood platelets of healthy donors and IHD patients was examined. The enzyme activity was found to be increased 3-fold in platelets possessing a high level of functional activity (IHD) and by one order of magnitude in patients with myocardial infarction as compared with healthy donors. An enzyme preparation possessing a phospholipase activity was isolated from platelets by using salt extraction (KCl) and sonication. Purification of the enzyme by affinity chromatography resulted in two protein peaks both having a phospholipase A2 activity, the purification and molecular masses of these fractions being 768- and 2200-fold, and 13.5 and 15 kDa, respectively. It was supposed that these proteins are substrate-specific forms of phospholipase A2.
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PMID:[Phospholipase A2 activity in human platelets. Isolation and purification of the enzyme]. 187 45

The alpha 1-adrenergic receptor exists as at least two distinct subtypes, alpha 1a and alpha 1b. Based on hydrophobic exclusion studies and limited proteolysis of the cloned receptor, it appears to possess characteristics analogous to other membrane-bound receptors including seven membrane spanning domains, three extracellular, and three intracellular loops, with extensive glycosylation near the extracellular amino terminus. Although the receptor is coupled to phospholipase C in cardiac myocytes, with activation resulting in the production of inositol trisphosphate (IP3) and diacylglycerol, recent findings suggest that the receptor may also be linked to phospholipase A2, phospholipase D, and cyclic nucleotide phosphodiesterase. The alpha 1-adrenergic receptor has been shown to increase in response to myocardial ischemia in a number of different species and to mediate not only positive inotropic effects, but also to contribute substantially to arrhythmogenesis. The increase in alpha 1-adrenergic receptors can also occur in isolated adult ventricular myocytes in response to hypoxia, a mechanism which appears to be secondary to the sarcolemmal accumulation of long-chain acylcarnitines. This increase in alpha 1-adrenergic receptors in hypoxic myocytes is also linked to an enhanced increase in IP3 in response to receptor stimulation. These and other findings obtained in vivo during ischemia suggest that alpha 1-adrenergic mechanisms can become prominent in myocardium under pathophysiologic conditions in which a depressed contractile state exists and may therefore serve as a secondary inotropic system. However, the arrhythmogenic effects of stimulation of the alpha 1-adrenergic receptor in the ischemic heart in man may contribute substantially to arrhythmogenesis and, thereby, to the incidence of sudden cardiac death.
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PMID:Modulation of alpha-adrenergic receptors and their intracellular coupling in the ischemic heart. 196 2

Recently, the prototype of a novel class of calcium-independent plasmalogen-selective phospholipase A2 activities was identified in the cytosolic fraction of canine myocardium (Wolf, R.A., and Gross, R.W. (1985) J. Biol. Chem. 260, 7295-7303) and subsequently purified and characterized (Hazen, S.L., Stuppy, R.J., and Gross, R.W. (1990) J. Biol. Chem. 265, 10622-10630). We now demonstrate that 15 min of myocardial ischemia utilizing a rabbit Langendorf perfused heart model results in a 10-fold increase in membrane-associated calcium-independent phospholipase A2 activity whose detection is entirely dependent upon utilization of plasmalogen substrate. Ischemia-induced phospholipase activity was identified as a membrane bound member of this class of phospholipases A2 by demonstration of: 1) concomitant production of lysoplasmenylcholine and sn-2 fatty acid from plasmenylcholine substrate; 2) maximal enzymatic activity in the absence of calcium ion; and 3) a 16-fold higher maximum reaction velocity utilizing plasmenylcholine compared to phosphatidylcholine substrate at multiple surface concentrations. Ischemia-induced phospholipase A2 activity was specifically localized to the microsomal fraction and could not be solubilized by sonication, salt treatment, exposure to chelators, or utilization of submicellar concentrations of detergent. The appearance of microsomal phospholipase A2 activity did not require ischemia-induced transcription or translation since identical increases in enzymic activity were obtained in hearts previously treated with actinomycin D and cycloheximide. Collectively, these results demonstrate that a membrane-associated calcium-independent phospholipase A2 that selectively hydrolyzes plasmalogen molecular species is the likely enzymic mediator of accelerated phospholipid catabolism during early myocardial ischemia.
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PMID:Activation of a membrane-associated phospholipase A2 during rabbit myocardial ischemia which is highly selective for plasmalogen substrate. 200 3

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. 203 71

Recent studies have demonstrated the existence of two members of a novel family of calcium-independent plasmalogen-selective phospholipases A2 in mammalian myocardium (Wolf, R. A., and R. W. Gross. 1985. J. Biol. Chem. 260:7295-7303; and Hazen, S. L., D. A. Ford, and R. W. Gross. 1991. J. Biol. Chem. 266:5629-5633). To examine the potential role of these calcium-independent phospholipases A2 in mediating membrane dysfunction during early myocardial ischemia, the temporal course of alterations in phospholipase A2 activity during global ischemia in Langendorf perfused rabbit hearts was quantified and compared with traditionally accepted markers of myocytic ischemic injury and anaerobic metabolism. We now report that membrane-associated calcium-independent plasmalogen-selective phospholipase A2 activity increased over 400% during 2 min of global ischemia (P less than 0.01), was near maximally activated (greater than 10-fold) after only 5 min of ischemia, and remained activated throughout the entire ischemic interval examined (2-60 min). Activation of membrane-associated plasmalogen-selective phospholipase A2 after 5 min of myocardial ischemia was rapidly reversible during reperfusion of ischemic tissue. Both the activation of phospholipase A2 and its reversibility during reperfusion were temporally correlated to alterations in myocytic anaerobic metabolism. Furthermore, activation of membrane-associated phospholipase A2 was essentially complete before electron microscopic evidence of cellular damage. Collectively, these results identify dynamic alterations in calcium-independent plasmalogen-selective phospholipase A2 activity during myocardial ischemia which precede irreversible cellular injury and demonstrate that activation of plasmalogen-selective phospholipase A2 is amongst the earliest biochemical alterations in ischemic myocardium.
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PMID:The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia. 205 26

Recently, we identified a novel calcium-independent, plasmalogen-selective phospholipase A2 activity in canine myocardial cytosol which represents the major measurable phospholipase A2 activity in myocardial homogenates (Wolf, R. A., and Gross, R. W. (1985) J. Biol. Chem. 260, 7295-7303). We now report the 154,000-fold purification of this phospholipase A2 to homogeneity through utilization of sequential anion exchange, chromatofocusing, affinity, Mono Q, and hydroxylapatite chromatographies. The purified enzyme had a molecular mass of 40 kDa, possessed a specific activity of 227 mumol/mg min, had a pH optimum of 6.4, and catalyzed the regiospecific cleavage of the sn-2 fatty acid from diradyl glycerophospholipids. The purified polypeptide was remarkable for its ability to selectively hydrolyze plasmenylcholine in homogeneous vesicles (subclass rank order: plasmenylcholine greater than alkyl-ether choline glycerophospholipid greater than phosphatidylcholine) as well as in mixed bilayers comprised of equimolar plasmenylcholine/phosphatidylcholine. Purified myocardial phospholipase A2 also possessed selectivity for hydrolysis of phospholipids containing arachidonic acid at the sn-2 position in comparison to oleic or palmitic acid. Taken together, these results constitute the first purification of a calcium-independent phospholipase with absolute regiospecificity for cleavage of the sn-2 acyl linkage in diradyl glycerophospholipids and demonstrate that myocardial phospholipase A2 has kinetic characteristics which are anticipated to result in the selective hydrolysis of sarcolemmal phospholipids during myocardial ischemia.
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PMID:Purification and characterization of canine myocardial cytosolic phospholipase A2. A calcium-independent phospholipase with absolute f1-2 regiospecificity for diradyl glycerophospholipids. 235 13

PAF is a phospholipid formed from the action of phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after phospholipase A2 activation. A potent lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of ischemia and conditions of circulatory shock. These effects appear to be especially relevant to the syndrome of MSOF during critical illness. All of the major criteria for validation of a shock factor have been fulfilled for PAF. First, PAF has been measured in biological fluid of animals during shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and traumatic shock, as well as acute myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in shock, such as myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory shock and organ ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that tumor necrosis factors (i.e., cachectin) stim
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PMID:Induction of tissue injury and altered cardiovascular performance by platelet-activating factor: relevance to multiple systems organ failure. 265 Aug 21

Recent studies have implicated accelerated sarcolemmal phospholipid catabolism as a mediator of the lethal sequelae of atherosclerotic heart disease. We have demonstrated that plasmalogens are the predominant phospholipid constituents of canine myocardium and that plasmalogens are hydrolyzed by a novel calcium independent plasmalogen selective phospholipase A2. Since the activities of phospholipases are modulated by the molecular dynamics and interfacial characteristics of their phospholipid substrates, we compared the molecular dynamics of plasmenylcholine and phosphatidylcholine vesicles by electron spin resonance spectroscopy and deuterium magnetic resonance spectroscopy. Plasmenylcholine vesicles have separate and distinct molecular dynamics in comparisons to their phosphatidylcholine counterparts as ascertained by substantial decreases in the angular fluctuations and motional velocities of probes attached to their sn-2 aliphatic constituents. Furthermore, since free radical oxidation of myocardial lipid constituents occurs during myocardial ischemia and reperfusion, we demonstrated that 1O2 mediated oxidation of plasmenylcholine resulted in the generation of several products which have chromatographic characteristics and molecular masses corresponding to 2-acyl lysophosphatide derivatives. Taken together, these studies underscore the biologic significance of the predominance of sarcolemmal plasmalogens present in mammalian myocardium and suggest that their catabolism by plasmalogen selective phospholipases and/or oxidative processes may contribute to the lethal sequelae of myocardial ischemia.
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PMID:Subcellular distribution, molecular dynamics and catabolism of plasmalogens in myocardium. 267 69

PAF is a phospholipid formed from the action of phospholipase A2 triggered by immunologic or hypoxic stimuli. PAF does not exist in its active form but rather is present as a storage product within cells, and is synthesized rapidly upon appropriate activation. PAF is a potent lipid mediator which is released by a variety of cell types in mammalian systems. PAF appears to be a particularly important mediator of myocardial ischemia and circulatory shock states in mammalian species. Moreover, since PAF releases other lipid mediators, it may have an "amplifier" role in the propagation of circulatory disease states.
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PMID:Platelet activating factor (PAF) and its role in cardiac injury. 267 33


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