Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kinetics of protein kinase C (PKC) translocation and down-regulation in the 20-day-old fetal brain following short and long episodes of maternal-fetal blood flow occlusion were examined. Restriction for up to 15 min increased the specific enzymatic activity in the membrane by 73%, indicative of translocation. After a 30-min restriction and a 2.5-h reperfusion the total PKC activity in the cytosol was reduced to approximately 50%, consistent with down-regulation/inactivation. The total membrane PKC activity remained unchanged. Several PKC isoenzymes, including alpha, beta 1, beta 2, epsilon, and zeta, but not gamma, were identified in the fetal brain on western blots using specific antibodies. Compared with postnatal day 15, a greater proportion of the fetal PKC isoforms, particularly alpha and epsilon, were membrane bound, alpha, beta 2, epsilon, and zeta, but not beta 1, were translocated into the membrane compartment after episodes of ischemia alone or ischemia and reperfusion. There were no major identifiable proteolytic fragments in the 50-kDa region. Major losses in the total enzymatic activity were encountered in both cytosol and membrane fractions after storage of the enzyme for 10 days at 4 degrees C. These losses were less profound in membrane fractions from ischemic than control animals, suggesting a relative sparing of activity in the membrane as a result of the insult. Preincubation of DEAE-purified PKC for 30 min at 50 degrees C resulted in enzyme inactivation. This was accompanied by a size reduction (approximately 2-5 kDa) in the gel migration of several isozymes in both cytosol and membrane fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Ischemia-triggered translocation and inactivation of protein kinase C isoforms in the fetal brain. 759 56

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
 ...
PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

To investigate how cardiac myocytes recover from a brief period of ischemia, we used a metabolic inhibition (MI) model, one of the in vitro ischemic models, of chick embryo ventricular myocytes, and examined the induction of immediate-early (IE) genes mRNAs and the activity of mitogen-activated protein (MAP) kinase. We performed Northern blot analysis to study the expression of c-jun, c-fos, and c-myc mRNAs during MI using 1 mM NaCN and 20 mM 2-deoxy-d-glucose, and also during the recovery from MI of 30 min. The c-fos mRNA was induced transiently at 30 and 60 min during the recovery. The expression of c-jun mRNA was significantly augmented at 30, 60, 90, and 120 min during the recovery (3.0-, 4.7-, 2.4-, and 1.9-fold induction, respectively) and so did the expression of c-myc mRNA (1.4-, 1.7-, 1.8-, and 2.0-fold induction, respectively). In contrast, the levels of these mRNAs remained unchanged during MI. The electrophoretic mobility shift assay revealed that AP-1 DNA binding activity markedly increased at 120 min during the recovery. When the cells were pretreated with protein kinase C (PKC) inhibitors, 100 microM H-7 or 1 microM staurosporine, the induction of c-jun mRNA at 60 min during the recovery was markedly suppressed (95 or 82% reduction, respectively). The c-jun induction was partially inhibited when the cells were treated with 2 mM EGTA during MI and the recovery (42% reduction). MAP kinase activity quantified with in-gel kinase assay was unchanged during MI, but significantly increased at 5, 10, and 15 min during the recovery (3.0-, 4.1-, and 3.4-fold increase, respectively). S6 kinase activity was also augmented significantly at 15 min during the recovery. Thus, these data suggest that IE genes as well as MAP kinase may play roles in the recovery process of cardiac myocytes from MI, and that the augmentation of c-jun expression needs the activation of PKC and to some extent, [Ca2+]i.
 ...
PMID:Immediate-early gene induction and MAP kinase activation during recovery from metabolic inhibition in cultured cardiac myocytes. 761 38

Platelet activating factor (PAF) is an important mediator of pulmonary microvascular endothelial cell (PMVEC) injury in sepsis. Membrane receptors for PAF have been identified on PMVECs and mediate its actions at least in part by protein kinase C activation. Since rolipram, a family IV cyclic AMP phosphodiesterase inhibitor, and isoproterenol, an adenylate cyclase activator, both reverse ischemia-reperfusion-induced lung permeability, we studied the effects of these agents on PAF-induced pulmonary microvascular permeability. The isolated rat lung model was used in which lungs were ventilated and buffer perfused at constant flow while suspended from a force transducer to monitor lung weight along with arterial (P(a)) and venous (Pv) pressures. Control lungs (n = 6) were infused with PAF (40 nmole/kg) via an arterial port and the capillary permeability coefficient (Kf,c) was determined at 0, 15, and 60 min. The remaining lungs were randomized for infusion with either rolipram (n = 4, 20 mumole/kg) or isoproterenol (n = 4, 5 mumole/kg) via an arterial port 30 min after injury with PAF. In the rolipram- and isoproterenol-treated groups, the Kf,c was determined 15 and 60 min postinfusion with these agents. The control group showed significant elevation in the Kf,c and total pulmonary resistance (Rt). At 15 and 60 min, rolipram and isoproterenol reversed PAF injury as shown by the significant improvement in the Kf,c and Rt. These findings support the concept that increased cyclic AMP is an important mediator in the reversal of PAF-increased PMVEC permeability and pulmonary resistance.
 ...
PMID:Rolipram and isoproterenol reverse platelet activating factor-induced increases in pulmonary microvascular permeability and vascular resistance. 763 Jan 21

Increased sympathetic activity has been documented in patients during acute myocardial infarction. Clinical and experimental studies have suggested that this increased sympatho-adrenergic activation may contribute to the development of lethal ventricular arrhythmias in the ischemic heart. In acute myocardial ischemia, adrenergic stimulation of the ischemic myocardium is independent of plasma catecholamines, since local catecholamine concentrations within the ischemic myocardium surpass plasma concentrations by several orders of magnitude. Both afferent and efferent autonomic nerves are activated immediately with myocardial ischemia. Poorly perfused myocardium, however, is protected within the first few minutes of ischemia, via several mechanisms, against high local concentrations of catecholamines. Ischemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release induced by central sympathetic stimulation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of myocardial ischemia to more than 10 min local nonexocytotic noradrenaline release prevails. This release is not prevented by the above-mentioned protective mechanisms and accounts for local extracellular catecholamine concentrations in the micromolar range, i.e., 100 to 1000 times higher than the normal plasma concentrations. It shows several features that make it possible to differentiate it from exocytotic release and to assign it to a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is independent of central sympathetic activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and is not accompanied by the release of sympathetic co-transmitters such as neuropeptide Y. It is however suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic sympathetic denervation effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release such as uptake1, blocking agents or sodium-proton exchange inhibitors effectively reduce the occurrence of ischemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic noradrenaline release in myocardial ischemia. At the postsynaptic side, catecholamines released during myocardial ischemia exert their effects by stimulating alpha- and beta-adrenergic receptors of cardiac myocytes. During acute myocardial ischemia the responsiveness of adrenergic receptors to stimulation by catecholamines is enhanced. Several studies have demonstrated an increase in functionally coupled beta-adrenergic receptor number during myocardial ischemia. Likewise, alpha 1-adrenergic responsivity increases in myocardium subjected to acute ischemia and contributes significantly to the arrhythmogenic effect of catecholamines.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Sympatho-adrenergic activation of the ischemic myocardium and its arrhythmogenic impact. 763 99

Bradykinin receptor activation has been proposed to be involved in ischemic preconditioning. In the present study, we further investigated the role of this agent in preconditioning in both isolated and in situ rabbit hearts. All hearts were subjected to 30 minutes of regional ischemia followed by reperfusion for 2 hours (in vitro hearts) and 3 hours (in situ hearts). Infarct size was measured by tetrazolium staining and expressed as a percentage of the size of the risk zone. Preconditioning in situ hearts with 5 minutes of ischemia and 10 minutes of reperfusion significantly reduced infarct size to 10.2 +/- 2.2% of the risk region (P < .0005 versus control infarct size of 36.7 +/- 2.6%). Pretreatment with HOE 140 (26 micrograms/kg), a bradykinin B2 receptor blocker, did not alter infarct size in nonpreconditioned hearts (40.6 +/- 5.3% infarction) but abolished protection from ischemic preconditioning (34.1 +/- 1.6% infarction). However, when HOE 140 was administered during the initial reflow period following 5 minutes of ischemia, protection was no longer abolished (15.6 +/- 3.9% infarction versus 13.3 +/- 3.8% without HOE 140, P = NS). Bradykinin infusion in isolated hearts mimicked preconditioning, and protection was not affected by pretreatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester or the prostaglandin synthesis inhibitor indomethacin but could be completely abolished by the protein kinase C (PKC) inhibitors polymyxin B and staurosporine as well as by HOE 140. HOE 140 could not block the protection of ischemic preconditioning in isolated hearts. That failure was apparently due to the absence of blood-borne kininogens rather than autonomic nerves. When the preconditioning stimulus in the in situ model was amplified with four cycles of 5-minute ischemia/10-minute reperfusion, HOE 140 pretreatment could no longer block protection (infarct size was 10.7 +/- 3.5% versus 6.4 +/- 2.0% without HOE 140, P = NS). We propose that bradykinin receptors protect by coupling to PKC as do adenosine receptors, and blockade of either receptor will diminish the total stimulus of PKC below threshold and prevent protection. A more intense preconditioning ischemic stimulus can overcome bradykinin receptor blockade, however, by simply enhancing the amount of adenosine and possibly other agonists released.
 ...
PMID:Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. 764 31

Circulating endothelin (ET) levels are elevated in conditions such as endotoxemia, hepatic ischemia-reperfusion injury, or orthotopic liver transplantation, and this potent peptide may contribute to hepatic pathophysiology. We measured the surface binding of [125I]ET-1 to rat Kupffer cells in primary culture at 4 degrees C; the dissociation constant (Kd) was 270 pmol/L, and the apparent Bmax was 3,000 receptors/cell. At 37 degrees C, total association (surface binding plus internalization) was much greater than at 4 degrees C, indicating that internalization of the receptor-ligand complex is rapid; the apparent Kd was 30 pmol/L, comparable with other reports for hepatic-derived cells. Studies using [125I]ET-1, [125I]ET-3, and specific ET (ant)agonists showed that Kupffer cells possess predominantly ET(B) type receptors. Prior treatment with 500 pmol/L unlabeled endothelin rapidly ( < 15 minutes) occluded 60% of subsequent [125I]ET association; using 5 nmol/L unlabeled ET, this occlusion occurred within 1 minute. [125I]ET association with Kupffer cells was unaffected by short-term (approximately 1 hour) treatment with cyclic adenosine monophosphate (cAMP), but long-term (20 hour) treatment resulted in a twofold increase in [125I]ET association with no change in the apparent Kd. Stimulation of protein kinase C in Kupffer cells by phorbol 12-myristate acetate had a dual regulatory effect on [125I]ET association. Short-term ( < 1 hour) treatment with phorbol 12-myristate acetate decreased [125I]ET-3 association by 50%, whereas prolonged treatment (20 hour) increased association twofold. In both cases, the apparent Kd for [125I]-endothelin was unaltered.
 ...
PMID:Endothelin association with the cultured rat Kupffer cell: characterization and regulation. 765 98

This study analyzed the ability of the N-methyl-D-aspartate receptor antagonist dextrorphan (DX) to prevent neuronal degeneration (analyzed by light microscopy), calmodulin (CaM) redistribution (analyzed by immunocytochemistry) and changes in activity of two major Ca(2+)-dependent protein kinases--calcium/calmodulin-dependent protein kinase II (CaM-KII) and protein kinase C (PKC) (analyzed by specific substrate phosphorylation) after 20 min of global ischemia (four-vessel occlusion model) in rats. DX treatment before and after ischemia significantly protected hippocampal and cortical neurons from neurodegeneration whereas DX posttreatment alone did not have any effect on preservation of neuronal morphology as compared with placebo treatment analyzed 72 h after 20 min of ischemia. Similarly to histological changes, DX exhibited protection against redistribution of CaM observed after ischemia. These changes were detected both in hippocampus as well as in cerebral cortex. Finally, DX administered before ligation of the carotid arteries reduced loss in both CaM-KII and PKC activity evoked by ischemia.
 ...
PMID:Neuronal protection and preservation of calcium/calmodulin-dependent protein kinase II and protein kinase C activity by dextrorphan treatment in global ischemia. 768 73

The effect of the platelet activating factor (PAF) antagonist BN52021 on [3H]D-aspartate (D-Asp) release was investigated in rat hippocampal slices during and after incubation (20 min) in ischaemia-like conditions. Ischaemia did not influence spontaneous D-Asp outflow whereas K(+)-evoked, calcium-dependent release was markedly enhanced in reoxygenated, post-ischaemic slices. These slices also showed a substantial translocation/activation of protein kinase C (PKC). BN52021 blocked both ischaemia-induced effects. Moreover, the PKC inhibitor H7 attenuated post-ischaemic K(+)-evoked D-Asp release when beta-PDBu, a PKC activator, was used to enhance the response of normoxic slices. Assuming that PKC is activated by ischaemia in a PAF-dependent manner and that this activation proceeds to enhanced glutamate exocytosis, we speculate on the involvement of PAF receptor stimulation in the pathology of cerebral ischaemia.
 ...
PMID:PAF antagonist, BN52021, inhibits [3H]D-aspartate release after ischaemia in vitro. 770 35

Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of vascular endothelial growth factor in cardiac myocytes. 772 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>