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)

Protein tyrosine kinases play important roles in the development of the mammalian nervous system during embryogenesis and in the maintenance of function of the adult brain. Using a semi-nested PCR technique based on a short amino acid motif of protein tyrosine kinases, we isolated a human genomic DNA encoding a peptide whose sequence was related to known mammalian protein tyrosine kinases. The expression was examined by Northern blot analysis, and transcripts were detected almost exclusively in the brain. The corresponding cDNA was sequenced, and it was revealed that the gene designated as byk coded for a receptor-like molecule with a motif of protein tyrosine kinase. Immunohistochemical analysis demonstrated that the Byk protein was expressed in neurons and was located in the nuclear envelope. To understand the physiological significance of the Byk protein, we investigated the behavior of this molecule in the hippocampus after ischemia. Byk-like immunoreactivity disappeared from the neurons in the fields CA1 through CA3 and the dentate gyrus of the hippocampus following 20 min of ischemia. After recirculation of blood flow, neurons in the CA3 field and the dentate gyrus re-expressed Byk-like antigen but CA1 neurons did not. Interestingly, Byk-like immunoreactivity was detected in microglial cells and astrocytes in the CA1 field that were activated after ischemia. Byk could be a new tool to study the neuron-glia and glia-glia interactions.
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PMID:A tyrosine kinase-like molecule is localized in the nuclear membrane of neurons: hippocampal behavior under stress. 917 67

Tyrosine-specific protein phosphorylation has been recently implicated in mediating pathological changes associated with cerebral ischemia. In the present study, acute hypoxia/ischemia (anoxia) was simulated in vitro by incubating rat hippocampal slices in glucose-free artificial cerebrospinal fluid saturated with 95% N2/5% CO2. A marked decrease in the level of tyrosine phosphorylation of many protein bands compared with the control was observed. Immunoprecipitation and western blot confirmed that the NR2A/2B subunits of the N-methyl-D-aspartate receptors are among the dephosphorylated proteins. Maximal dephosphorylation of bands corresponding to NR2A/2B was reached after 10 min, and no recovery was observed even after 1 h in normal, oxygenated artificial cerebrospinal fluid. The effect was partially blocked by dephostatin, a membrane-permeable inhibitor of protein tyrosine phosphatases, but was not affected by the presence of glutamate receptor antagonists, or by removing extracellular Ca2+ or chelating intracellular Ca2+. Enzyme assay showed that anoxic stimulation resulted in a selective reduction in protein tyrosine kinase activity without affecting protein tyrosine phosphatase activity. Thus the present work suggests that anoxic stimulation produces a selective inhibition of protein tyrosine kinase activity leading to tyrosine-dephosphorylation of several proteins including the N-methyl-D-aspartate receptors. The underlying mechanism may involve a novel signal transduction pathway, which may protect neurons from degeneration during ischemic stress.
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PMID:Reduction of tyrosine kinase activity and protein tyrosine dephosphorylation by anoxic stimulation in vitro. 948 12

In rabbits, inhibition of either protein kinase C or protein tyrosine kinase abolishes the infarct size reduction achieved by ischemic preconditioning. In pigs, however, inhibition of protein kinase C does not attenuate ischemic preconditioning. The present study tested whether inhibition of protein tyrosine kinase alone or in combination with inhibition of protein kinase C interferes with ischemic preconditioning in pigs. In 29 enflurane-anesthetized pigs, the LAD was cannulated and perfused from an extracorporeal circuit. Protein tyrosine kinase and protein kinase C were inhibited by continuous intracoronary infusion of genistein (5x10(-6) mol/l) and staurosporine (10(-7) mol/l), respectively. Subendocardial blood flow (ENDO) was measured with microspheres. Infarct size was analysed by TTC staining (% of LV area at risk) following 90 min low-flow ischemia and 120 min reperfusion. In the presence of genistein, 90 min ischemia at an ENDO of 0.06+/-0.01 (+/-s.e.m.) ml/min/g resulted in an infarct size of 16.7+/-4.2% (n=8). With genistein, ischemic preconditioning by 10 min ischemia and 15 min reperfusion still reduced infarct size to 6.5+/-2.7% (ENDO: 0.05+/-0. 01 ml/min/g, n=7, P<0.05). In the presence of both genistein and staurosporine, infarct size following 90 min ischemia was 14.1+/-3. 6% (ENDO: 0.06+/-0.01 ml/min/g, n=7). With genistein and staurosporine, ischemic preconditioning no longer reduced infarct size significantly (11.5+/-3.1%, ENDO: 0.06+/-0.01 ml/min/g, n=7). The effective attenuation of ischemic preconditioning only by simultaneous inhibition of both, protein kinase C and protein tyrosine kinase, suggests a complex signal cascade involving both protein kinases.
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PMID:Prevention of ischemic preconditioning only by combined inhibition of protein kinase C and protein tyrosine kinase in pigs. 951 96

Loss of amino acids into the coronary artery perfusate, which is exacerbated during anoxic stress, may have important implications for the ability of hearts subjected to ischemia or anoxia to recover function during reoxygenation. This work investigates the mechanisms underlying the amino acid efflux. Rat Langendorff heart preparations were used to study amino acid loss into coronary artery perfusates during anoxia or anoxia/reoxygenation sequences. Coronary flow rates, heart rates and intra-aortic pressures were recorded. Changes in myocardial amino acid concentrations were equated with amino acid levels in collected anoxic perfusate. With the exception of taurine, the differences in amino acid levels between normoxic and anoxic hearts were smaller than the amounts lost into the coronary perfusates, indicating ongoing replenishment of most amino acids during the anoxic episode. Fifteen-minute periods of exposure to low oxygen levels (P02 18-20 mmHg) resulted in large percentage increases in perfusate amino acid levels which returned slowly towards control levels upon reoxygenation. Anion channel blockers, anthracene-9-carboxylic acid, furosemide, and 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonic acid (SITS), depressed anoxia-elicited increases in amino acid release. Phospholipase inhibition with quinacrine, 4-bromophenacyl bromide and 7,7-dimethyl-eicosadenoic acid (DEDA) depressed the anoxia-evoked release of amino acids. Combined applications of SITS and DEDA exhibited additive effects, virtually abolishing anoxia-evoked release of all the amino acids. The protein kinase C inhibitor, chelerythrine chloride, and the protein tyrosine kinase inhibitors, genistein and lavendustin A, inhibited anoxia-evoked amino acid release. Polyunsaturated fatty acids, arachidonic and linoleic, reduced anoxia-evoked amino acid release whereas monosaturated (oleic) and saturated (stearic) acids were ineffective. The glutamate transport inhibitor, dihydrokainate, depressed anoxia-evoked glutamate and aspartate release. These results suggest that at least three possible mechanisms for the anoxia-evoked amino acid efflux including (a) diffusional release through volume activated anion channels, (b) leakage across myocyte plasma membranes as a consequence of phospholipase activation and (c) reversal of Na+ dependent high-affinity transporters.
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PMID:Mechanisms of amino acid release from the isolated anoxic/reperfused rat heart. 972 Oct 23

Myocardial adaptation to ischemia has been shown to activate protein tyrosine kinase, potentiating activation of phospholipase D, which leads to the stimulation of mitogen-activated protein (MAP) kinases and MAP kinase-activated protein (MAPKAP) kinase 2. The present study sought to further examine the signal transduction pathway for the MAPKAP kinase 2 activation during ischemic adaptation. Isolated perfused rat hearts were adapted to ischemic stress by repeated ischemia and reperfusion. Hearts were pretreated with genistein to block tyrosine kinase, whereas SB-203580 was used to inhibit p38 MAP kinases. Western blot analysis demonstrated that p38 MAP kinase is phosphorylated during ischemic stress adaptation. Phosphorylation of p38 MAP kinase was blocked by genistein, suggesting that activation of p38 MAP kinase during ischemic adaptation is mediated by a tyrosine kinase signaling pathway. MAPKAP kinase 2 was estimated by following in vitro phosphorylation with recombinant human heat shock protein 27 as specific substrate for MAPKAP kinase 2. Again, both genistein and SB-203580 blocked the activation of MAPKAP kinase 2 during myocardial adaptation to ischemia. Immunofluorescence microscopy with anti-p38-antibody revealed that p38 MAP kinase is primarily localized in perinuclear regions. p38 MAP kinase moves to the nucleus after ischemic stress adaptation. After ischemia and reperfusion, cytoplasmic striations in the myocytes become obvious, indicating translocation of p38 MAP kinase from nucleus to cytoplasm. Corroborating these results, myocardial adaptation to ischemia improved the left ventricular functions and reduced myocardial infarction that were reversed by blocking either tyrosine kinase or p38 MAP kinase. These results demonstrate that myocardial adaptation to ischemia triggers a tyrosine kinase-regulated signaling pathway, leading to the translocation and activation of p38 MAP kinase and implicating a role for MAPKAP kinase 2.
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PMID:Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. 981 94

Transient cerebral ischemia results in an increase in the tyrosine phosphorylation of proteins associated with postsynaptic densities (PSDs). The authors investigated the possible mechanisms behind this increase by analyzing isolated PSDs for protein tyrosine kinase activity and for the presence of specific tyrosine kinases. Transient (15 minutes) global ischemia was produced in adult rats by four-vessel occlusion, and PSDs were isolated immediately after ischemia or after 20 minutes or 6 hours of reperfusion. Tyrosine phosphorylation of several PSD proteins, including the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, was enhanced relative to shams after 20 minutes of reperfusion and underwent a further increase between 20 minutes and 6 hours. The ability of intrinsic PSD tyrosine kinase to phosphorylate PSD proteins, including the NMDA receptor, increased threefold after ischemia. Whereas PSD-associated proline-rich tyrosine kinase 2 (PYK2) and gp145TrkB were elevated immediately after the ischemic event, increases in Src and Fyn were not apparent until 6 hours of reperfusion. The level of PSD-associated pp125FAK decreased after ischemia. The results demonstrate that ischemia results in selective changes in the association of protein tyrosine kinases with the PSD which may account for ischemia-induced increases in the tyrosine phosphorylation of PSD proteins.
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PMID:Altered association of protein tyrosine kinases with postsynaptic densities after transient cerebral ischemia in the rat brain. 1072 15

Myocardial dysfunction after hypothermic protection has been linked to various mechanisms. Coronary vasospasm in particular may be responsible for ischemic injury during reperfusion. Herein we hypothesized that coronary arteries (CA) sustain a cold-induced contraction during hypothermia mediated by a protein tyrosine kinase (PTK)-/protein tyrosine phosphatase (PTP)-dependent pathway. Isolated newborn lamb CA rings were studied in a tissue bath for isometric contraction during 2-h profound (17 degrees C) or ultra-profound (7 degrees C) hypothermia. In parallel, protein tyrosine phosphorylation was evaluated by use of the Western blot technique. Na-orthovanadate (SOV) and genestein (GEN) were used separately and in combination to evaluate the effect of PTK/PTP activation on CA contraction and tyrosine phosphorylation during cooling (17 or 7 degrees C) vs 37 degrees C. Cooling from 37 to 7 degrees C induced transient contraction at approximately 17 degrees C (29% KCl response), which was more prominent during rewarming to 37 degrees C (36% KCl). Cooling to 17 degrees C resulted in sustained contraction (7-10% KCl), which was reversible upon rewarming. Cold-induced contraction was significantly enhanced by SOV (7- to 10-fold at 17 degrees C; 2-fold at 7 degrees C) and abolished by GEN. Concurrently, tyrosine phosphorylation of 33-, 45-, and 104-kDa proteins increased during cooling (35-100% at 17 degrees C; 46-66% at 7 degrees C). Tyrosine phosphorylation was similarly enhanced by SOV (1.7- to 2.3-fold at 17 degrees C; 2.9- to 3.9-fold at 7 degrees C) and abolished by GEN in the presence or absence of SOV. These results support a prominent role for the PTK/PTP signal transduction pathway in the coronary artery cold-induced contraction. This information provides one possible biomolecular mechanism linked to ischemia/reperfusion pathophysiology of CA in neonatal hearts exposed to hypothermic myocardial protection.
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PMID:Phosphorylation in coronary artery cold-induced contraction in the newborn lamb. 1133 88

Recent studies reveal that brief ethanol exposure induces cardioprotection against simulated ischemia in cardiomyocytes by the activation of protein kinase C- epsilon. The present study tests the ability of ethanol to induce protection in rabbit hearts in which infarct size was the end-point and explores the signal transduction pathways involved. In isolated rabbit hearts, 50 m m ethanol infused for 5 min with 10 min of washout prior to 30 min of regional ischemia reduced infarct size (triphenyltetrazolium chloride staining) by 49%. Neither adenosine receptor blockade with 8-(p -sulfophenyl) theophylline nor the free radical scavenger N-2-mercaptopropionyl glycine inhibited the protection triggered by ethanol. In contrast, protein kinase C inhibition with chelerythrine, protein tyrosine kinase inhibition with genistein, and blockade of ATP-sensitive potassium channels (K(ATP)) with either 5-hydroxydecanoate or glibenclamide did abolish protection. Thus, transient ethanol exposure followed by washout prior to ischemia elicits a preconditioning-like effect involving protein kinase C, at least one protein tyrosine kinase, and K(ATP)channels, but neither adenosine nor free radicals.
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PMID:Acute alcohol-induced protection against infarction in rabbit hearts: differences from and similarities to ischemic preconditioning. 1170 45

Recent data indicate that acute alcohol exposure can have a preconditioning-like protective effect on the heart. We investigated the effect of ethanol exposure shortly before regional ischemia in an infarct model. Both in the open-chest rabbit and in the isolated rabbit heart, exposure of the heart to ethanol significantly reduced infarct size, but only if the alcohol were washed out or sufficiently metabolized before the onset of ischemia. If ethanol were still present during ischemia, it could not only prevent its own protective effect, but also abolish protection induced by ischemic preconditioning or the mitochondrial K(ATP) channel activator diazoxide. In the in vitro model, we tested for possible mediators of ethanol-induced protection and made comparisons to the signaling cascade of ischemic preconditioning. Neither adenosine receptor blockade with 8-(p-sulfophenyl) theophylline, scavenging of free radicals with N-2-mercaptopropionyl glycine, nor closure of K(ATP) channels with glibenclamide affected ethanol's protective effect. However, either a PKC inhibitor or a protein tyrosine kinase inhibitor could completely block ethanol-induced infarct size reduction. Both the protective and anti-protective effects of ethanol had a threshold of about 5 mM. Thus, ethanol-induced protection is mediated by protein kinase C and at least one protein tyrosine kinase, but, in contrast to ischemic preconditioning, is not triggered by either adenosine receptors, free radicals, or K(ATP) channels. Ethanol can only exert its protective effect if it is removed before the onset of ischemia. If still present during ischemia, ethanol has the opposite effect, and inhibits preconditioning by an as yet unidentified mechanism.
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PMID:The protective and anti-protective effects of ethanol in a myocardial infarct model. 1207 65

Although Src protein tyrosine kinases (PTKs) have been shown to be essential in late preconditioning (PC) against myocardial stunning, their role in triggering versus mediating late PC against myocardial infarction remains unclear. Four groups of conscious rabbits were subjected to a 30-min coronary occlusion on day 2, with or without PC ischemia on day 1. Administration of the Src PTK inhibitor lavendustin A (LD-A; 1 mg/kg iv) before the PC ischemia on day 1 (group III, n = 7) failed to block the delayed protective effect against myocardial infarction 24 h later. Late PC against infarction, however, was completely abrogated when LD-A was given 24 h after the PC ischemia, prior to the 30-min occlusion on day 2 (group IV, n = 8). We conclude that, in conscious rabbits, Src PTK activity is necessary for the mediation of late PC protection against myocardial infarction on day 2, but not for the initiation of this phenomenon on day 1. Taken together with previous studies in the setting of stunning, these findings reveal heretofore unrecognized differences in the roles of Src PTKs in late PC against stunning versus late PC against infarction.
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PMID:Role of Src protein tyrosine kinases in late preconditioning against myocardial infarction. 1212


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