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)

Cardiac sarcolemmal Na(+)/H(+) exchange is critical for the regulation of intracellular pH, and its activity contributes to ischemia-reperfusion injury. It has been suggested that the membrane phospholipid environment does not modulate Na(+)/H(+) exchange. The present study was carried out to determine the effects on Na(+)/H(+) exchange of modifying the endogenous membrane phospholipids through the addition of exogenous phospholipase D. Incubation of 0.825 U of phospholipase D with 1 mg of porcine cardiac sarcolemmal vesicles hydrolyzed 34 +/- 2% of the sarcolemmal phosphatidylcholine and increased phosphatidic acid 10.2 +/- 0.5-fold. Treatment of vesicles with phospholipase D resulted in a 46 +/- 2% inhibition of Na(+)/H(+) exchange. Na(+)/H(+) exchange was measured as a function of reaction time, extravesicular pH, and extravesicular Na(+). All of these parameters of Na(+)/H(+) exchange were inhibited following phospholipase D treatment compared with untreated controls. Passive efflux of Na(+) was unaffected. Treatment of sarcolemmal vesicles with phospholipase C had no effect on Na(+)/H(+) exchange. We conclude that phospholipase D-induced changes in the cardiac sarcolemmal membrane phospholipid environment alter Na(+)/H(+) exchange.
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PMID:Altered cardiac Na(+)/H(+) exchange in phospholipase D-treated sarcolemmal vesicles. 1099 82

3,5-dihydroxyphenylglycine (3,5-DHPG) was the first agonist shown to be group I metabotropic glutamate receptor selective with its agonist effects residing exclusively in the S-isomer. Some results suggest that (S)-3,5-DHPG may be a partial agonist of mGluR1a and mGluR5a in neurons and astrocytes. It has been reported that (S)-3,5-DHPG can, under certain conditions, interact with NMDA receptors. (S)-3,5-DHPG exerts different effects on second messengers in adult and neonatal tissues. It stimulates phosphoinositide hydrolysis in a dose-dependent manner in both the adult and neonate hippocampus, inhibits stimulated cAMP levels in the adult and enhances the cAMP in the neonate. It is an effective antagonist of mGluRs linked to phospholipase D (PLD) in the adult and an agonist in the neonate brain or astrocyte cultures. (S)-3,5-DHPG induces elevation of [Ca2+]i and regulates multiple subtypes of Ca2+ channels. This agonist of group I mGluRs may modulate neurotransmitters release, reflecting the diversity of mechanisms involved. Depending on the dose, (S)-3,5-DHPG enhances or decreases excitatory postsynaptic potentials (EPSPs) and under appropriate conditions it can induce long-term depression (LTD) and long-term potentiation (LTP). Some studies suggested a therapeutic role for (S)-3,5-DHPG in neuronal injury, regulation of intestinal motility and secretion, learning and memory processes and in cardiovascular system. (S)-3,5-DHPG may be useful as a cognitive enhancing agent in memory impairment associated with ischemia or hypoxia. Recent investigations suggested possible beneficial effects of (S)-3,5-DHPG in Alzheimer's disease.
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PMID:(S)-3,5-DHPG: a review. 1207 May 29

Phosphatidylalcohols, such as phosphatidylethanol (PEth), are formed from phosphatidylcholine in the presence of a primary alcohol (e.g., ethanol). This 'transphosphatidylation' reaction is used as specific phospholipase D (PLD) assay. Accumulation of PEth in tissues is recognized as a reliable measure of PLD activity, as PEth is allegedly metabolically stable. The general validity of this assumption was reinvestigated in isolated rat heart, small intestine and brain slices. The half-times of 3H-PEth degradation (labelled with 3H-myristic acid and preformed by ethanol exposure for 30 min) were about 1 h in heart and small intestine, but 17 h in brain. As the formation of PEth is superimposed by simultaneous degradation, a mathematical model was established to calculate the differences between 'true' and 'apparent' PEth formation. As expected, this difference was relevant in heart and intestine, but not in brain tissue. For example, ischemia in the perfused heart for 30 min reversibly blocked PEth degradation and seemingly enhanced PEth formation; the block was reversed by ischemic preconditioning (IPC) and by pretreatment with diazoxide, an opener of mitochondrial K(ATP) channels. In conclusion, PEth degradation in heart was energy-dependent and rapid, which, when ignored, may lead to misinterpretation of PEth values with respect to PLD activity.
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PMID:Degradation of phosphatidylethanol counteracts the apparent phospholipase D-mediated formation in heart and other organs. 1288 Aug 67

Activation of adenosine A1 or A3 receptors protects heart cells from ischemia-induced injury. The A3 receptor signals via RhoA and phospholipase D (PLD) to induce cardioprotection. The objective of the study was to investigate how RhoA activates PLD to achieve the anti-ischemic effect of adenosine A3 receptors. In an established cardiac myocyte model of preconditioning using the cultured chick embryo heart cells, overexpression of the RhoA-noninteracting PLD1 mutant I870R selectively blocked the A3 agonist (Cl-IBMECA, 10 nM)-induced cardioprotection. I870R caused a significantly higher percentage of cardiac cells killed in A3 agonist-treated than in A1 agonist (CCPA, 10 nM)-treated myocytes (ANOVA and posttest comparison, P<0.01). Consistent with its inhibitory effect on the PLD activity, I870R attenuated the Cl-IBMECA-mediated PLD activation. Cl-IBMECA caused a 41 +/- 15% increase in PLD activity in mock-transfected myocytes (P<0.01, paired t test) while having only a slight stimulatory effect on the PLD activity in I870R-transfected cells. To further test the anti-ischemic role of a direct RhoA-PLD1 interaction, atrial cardiac myocytes were rendered null for native adenosine receptors by treatment with irreversible A1 antagonist m-DITC-XAC and were selectively transfected with the human adenosine A1 or A3 receptor cDNA individually or they were cotransfected with cDNAs encoding either receptor plus I870R. I870R preferentially inhibited the human A3 receptor-mediated protection from ischemia. The RhoA-noninteracting PLD1 mutant caused a significantly higher percentage of cardiac cells killed in myocytes cotransfected with the human A3 receptor than in those cells expressing the human A1 receptor (ANOVA and posttest comparison, P<0.01). The present data provided the first demonstration of a novel physiological role for the direct RhoA-PLD1 interaction, that of potent protection from cardiac ischemia. The study further supported the concept that a divergent signaling mechanism mediates the anti-ischemic effect of adenosine A1 and A3 receptors.
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PMID:Role of direct RhoA-phospholipase D1 interaction in mediating adenosine-induced protection from cardiac ischemia. 1468 4

The release of choline as a water-soluble product of phospholipid hydrolysis was measured in the perfusate of rat hearts to monitor ischemic membrane degradation and its protection by ischemic preconditioning (IPC). Hearts were subjected to global ischemia (GI; 30 min of no-flow) followed by 60 min of reperfusion. To induce IPC, GI was preceded by four no-flow episodes of 5 min each. Deleterious consequences of GI and reperfusion, namely coronary flow reduction, incidence of arrhythmias and release of cardiac troponin T, were significantly attenuated by IPC. The release of choline increased during reperfusion in a biphasic manner: a first phase peaked immediately after GI and was followed by a second, delayed phase indicating choline release caused during reperfusion. Only the second phase was blocked by both IPC and by AACOCF3 (5 microM), an inhibitor of cytosolic phospholipase A2. The activity of phospholipase D (PLD) was unchanged after GI or IPC or GI plus IPC. In conclusion, choline release into heart perfusate was found to be a useful real-time indicator of phospholipid degradation caused by GI and by reperfusion and its protection by IPC. The results supplement previous observations on the accumulation of fatty acids in the phospholipid pool. There was no evidence for PLD activation by GI or IPC.
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PMID:Release of choline in the isolated heart, an indicator of ischemic phospholipid degradation and its protection by ischemic preconditioning: no evidence for a role of phospholipase D. 1526 65

Endogenous levels of the endocannabinoid anandamide, and the activities of the synthesizing and hydrolyzing enzymes, i.e. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, respectively, were determined in the cortex and the striatum of rats subjected to transient middle cerebral artery occlusion. Anandamide content was markedly increased ( approximately 3-fold over controls; P < 0.01) in the ischemic striatum after 2 h of middle cerebral artery occlusion, but not in the cortex, and this elevation was paralleled by increased activity of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D ( approximately 1.7-fold; P < 0.01), and reduced activity ( approximately 0.6-fold; P < 0.01) and expression ( approximately 0.7-fold; P < 0.05) of fatty acid amide hydrolase. These effects of middle cerebral artery occlusion were further potentiated by 1 h of reperfusion, whereas anandamide binding to type 1 cannabinoid and type 1 vanilloid receptors was not affected significantly by the ischemic insult. Additionally, the cannabinoid type 1 receptor antagonist SR141716, but not the receptor agonist R-(+)-WIN55,212-2, significantly reduced (33%; P < 0.05) cerebral infarct volume detected 22 h after the beginning of reperfusion. A neuroprotective intraperitoneal dose of 17beta-estradiol (0.20 mg x kg(-1)) that reduced infarct size by 43% also minimized the effect of brain ischemia on the endocannabinoid system, in an estrogen receptor-dependent manner. In conclusion, we show that the endocannabinoid system is implicated in the pathophysiology of transient middle cerebral artery occlusion-induced brain damage, and that neuroprotection afforded by estrogen is coincident with a re-establishment of anandamide levels in the ischemic striatum through a mechanism that needs to be investigated further.
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PMID:Modulation of the endocannabinoid system by focal brain ischemia in the rat is involved in neuroprotection afforded by 17beta-estradiol. 1766 9

The N-acylethanolamines (NAEs) and 2-arachidonoylglycerol (2-AG) are bioactive lipids that can modulate inflammatory responses and protect neurons against glutamatergic excitotoxicity. We have used a model of focal cerebral ischemia in young adult mice to investigate the relationship between focal cerebral ischemia and endogenous NAEs. Over the first 24 h after induction of permanent middle cerebral artery occlusion, we observed a time-dependent increase in all the investigated NAEs, except for anandamide. Moreover, we found an accumulation of 2-AG at 4 h that returned to basal level 12 h after induction of ischemia. Accumulation of NAEs did not depend on regulation of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D or fatty acid amide hydrolase. Treatment with the fatty acid amide hydrolase inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester; 1 mg/kg; i.p.) 1.5 h before arterial occlusion decreased the infarct volume in our model system. Our results suggest that NAEs and 2-AG may be involved in regulation of neuroprotection during focal cerebral ischemia in mice.
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PMID:Changes in brain levels of N-acylethanolamines and 2-arachidonoylglycerol in focal cerebral ischemia in mice. 1786 6

Cardiolipin (CL) is a phospholipid, which is exclusively located in mitochondria, and has a unique structure that consists of 2 phosphate residues and 4 kinds of fatty acyl chains. Cardiolipin plays an important role in regulating various kinds of mitochondrial proteins such as electron transport complexes, carrier proteins and phosphate kinases, and is also essential for the organization of particular mitochondrial structures such as cristae and contact sites. Mitochondrial phospholipase D hydrolyzes CL to produce phosphatidic acid, which is required for mitochondrial fusion. Oxidative stress-induced peroxidation of CL occurs because CL is rich in polyunsaturated fatty acids, especially linoleic acid. Accumulation of CL hydroperoxide (CLOOH) triggers the initiation of apoptosis. Formation of CLOOH causes the release of proapoptotic factors such as cytochrome c from the inner mitochondrial membrane and triggers opening of the permeability transition pore. Levels of CL decrease in the heart following ischemia or disease. Apoptosis is enhanced in temperature-dependent mutant cells whose amounts of CL reduce to half when compared to that of wild type cells. Low levels of CL cause the accumulation of CLOOH and enhance sensitivity to apoptosis. Accumulation of CLOOH in mitochondria causes instability of the membrane, because swelling of mitochondria is induced by the presence of CLOOH in the membrane and is significantly enhanced in CLOOH-loaded mitochondria by the addition of inducer of swelling.
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PMID:[Metabolism and biological function of cardiolipin]. 2364 97

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the salvage pathway of nicotinamide adenine dinucleotide synthesis. NAMPT can also be secreted and functions as a cytokine. We have previously shown that in the brain, NAMPT expression and secretion can be induced in microglia upon neuroinflammation and injury. Yet the mechanism for NAMPT secretion remains unclear. Here we show that NAMPT can be actively secreted from microglia upon the treatment of ischemia-like injury - oxygen-glucose deprivation and recovery (OGD/R). We confirmed that classical ER-Golgi pathway is not involved in NAMPT secretion. NAMPT secretion was further enhanced by ATP, and the secretion was mediated by P2X7 receptor and by intracellular Ca2+ . Importantly, we found that phospholipase D inhibitor, n-butanol, phospholipase D siRNA, and wortmannin significantly decreased OGD/R-induced and ATP-enhanced release of NAMPT in microglia. After excluding the mechanisms of involving secretory autophagy, endosomes, and secretory lysosome, we have concluded that microglial NAMPT is secreted mainly via exosome. Immune-electron microscopy identifies NAMPT in extracellular vesicles with the size and morphology characteristic of exosome. With the vesicles harvested by ultra-centrifugation, exosomal NAMPT is further confirmed by Western blotting analysis. Intriguingly, the amount of NAMPT relative to exosomal protein markers remains unchanged upon the treatment of OGD/R, suggesting a constant load of exosomal NAMPT in microglia. Taken together, we have identified NAMPT is actively secreted via exosome from microglia during neuroinflammation of ischemic injury.
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PMID:Nicotinamide phosphoribosyltransferase secreted from microglia via exosome during ischemic injury. 3126 39

A successful acute inflammatory response results in the elimination of infectious agents by neutrophils and monocytes, followed by resolution and repair through tissue-resident and recruited macrophages. Resolvins (D-series and E-series) are pro-resolving lipid mediators involved in resolution and tissue repair, whose intracellular signaling remains of interest. Here, we report that D-series resolvins (RvD1- RvD5) activate phospholipase D (PLD), a ubiquitously expressed membrane lipase enzyme activity in modulating phagocyte functions. The mechanism for PLD-mediated actions of Resolvin-D5 (RvD5) in polarizing macrophages (M1-like toward M2-like) was found to be two-pronged: (a) RvD5 inhibits post-transcriptional modifications, by miRs and 3'exonucleases that process PLD2 mRNA, thus increasing PLD2 expression and activity; and (b) RvD5 enhances PLD2-S6Kinase signaling required for membrane expansion and efferocytosis. In an in vivo model of second organ reflow injury, we found that RvD5 did not reduce lung neutrophil myeloperoxidase levels in PLD2-/- mice compared to WT and PLD1-/- mice, confirming a novel role of PLD2 as the isoform in RvD5-mediated resolution processes. These results demonstrate that RvD5-PLD2 are attractive targets for therapeutic interventions in vascular inflammation such as ischemia-reperfusion injury and cardiovascular diseases.
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PMID:D-series Resolvins activate Phospholipase D in phagocytes during inflammation and resolution. 3304 59


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