EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigated whether protein kinase C (PKC) plays a role in ischemic preconditioning in the rat heart. Chelerythrine, a specific antagonist of PKC, and 1,2-dioctanoyl-sn-glycerol (DOG), a diacylglycerol analogue and specific antagonist of PKC, were used to determine whether preconditioning could be blocked or triggered, respectively. Sprague-Dawley rats were anesthetized and instrumented for coronary occlusion and reperfusion. All animals were subjected to 45 minutes of regional ischemia (ISC) followed by 2.5 hours of reperfusion. The preconditioning protocol consisted of 5 minutes of ischemia and then 10 minutes of reperfusion. There were six groups: (1) control (group C, n = 5), (2) preconditioned and ISC (group PC, n = 6), (3) chelerythrine given 2 minutes before ISC (group CC, n = 5), (4) preconditioned and chelerythrine given 2 minutes before ISC (group PCC, n = 6), (5) DOG (dissolved in dimethylsulfoxide [DMSO]) given 10 minutes before ISC (group CD, n = 5), and (6) DMSO given 10 minutes before ISC (group DMSO, n = 3). The end point was infarct size measured using triphenyl tetrazolium chloride and expressed as a percentage of the volume at risk (I/R), measured with fluorescent particles. I/R was significantly reduced by preconditioning (group C, 58.6 +/- 5.0%; group PC, 32.7 +/- 6.3%; P < .01) and by the PKC agonist DOG, which reduced I/R to a similar extent as preconditioning (group C, 58.6 +/- 5.0%; group CD, 28.0 +/- 7.0%; P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C. Its role in ischemic preconditioning in the rat. 806 29

We used three interventions to test critically the theory that ischemic preconditioning is the result of translocation of cytosolic protein kinase C (PKC) into the membranes where it can be activated. If that theory were true then kinase activity should not be necessary during the preconditioning ischemia and thus blocking kinase activity at this time should not block protection. Secondly, since most translocation processes in the cell are accomplished by cytoskeletal microtubules, disrupting them with colchicine should also block protection from preconditioning. Finally, translocating PKC by transient exposure to PMA, should still require adenosine receptor activation to reactivate the PKC pathway during the subsequent ischemia. Blocking kinase activity with staurosporine during a 30 min insult completely blocks protection in preconditioned hearts but when staurosporine treatment was confined to the preconditioning episode protection was not blocked in five of the eight hearts studied. Microtubule disruption with colchincine did block the protective effect of preconditioning (38.3 +/- 1.9% infarction v 40.6 +/- 4.1% in non-preconditioned). Colchicine had no effect on infarct size in the non-preconditioned group. Five min PMA treatment plus 10 min washout significantly limited infarct size in isolated rabbit hearts subjected to 30 min regional ischemia (5.9 +/- 1.1% v 31 +/- 3.5% infarction in control). PMA's protection was blocked by adding the adenosine receptor blocker, SPT, during the sustained ischemia (38.1 +/- 6.1% infarction). All three of these experiments strongly support the translocation theory of ischemic preconditioning.
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PMID:Evidence that translocation of protein kinase C is a key event during ischemic preconditioning of rabbit myocardium. 807 20

Autoradiographic visualization of the Bmax (maximal binding capacity) and Kd (dissociation constant) of [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]forskolin (FK) was performed after 30-min unilateral carotid artery occlusion in the gerbil brain. These parameters and the local cerebral blood flow (CBF) were measured at the level of the caudate-putamen in the same brain using a digital image processing technique developed in our laboratory. The local CBF was measured at the end of the experiment. [3H]PDBu and [3H]FK were utilized as specific ligands to assess the activities of protein kinase C (PKC) and adenylate cyclase (AC), respectively. The local CBF on the occluded side was severely reduced and ranged from 0.2 to 9.0 ml/100 g/min, whereas the local CBF on the non-occluded side exhibited a moderate reduction except in the midline regions. The Bmax values of PDBu and FK were significantly increased not only on the occluded side but also on the non-occluded side in the ischemia group as compared to the corresponding values in the sham group. In contrast, the Kd value of each ligand remained unchanged in the ischemia group. These findings suggest that both the adenylate cyclase and protein kinase C systems may be significantly and diffusely activated in the initial stage of brain ischemia. Thus, severe hemispheric cerebral ischemia in the acute phase may induce severe perturbation of the second messenger systems in extensive bilateral regions.
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PMID:Enhanced maximal binding capacity (Bmax) of second messenger ligand in the acute phase of cerebral ischemia--direct visualization by digital image analysis. 809 Mar 67

There is now convincing evidence that excessive accumulation of the excitatory amino acid glutamate (Glu) in the extracellular space is toxic to neurons. However, the regulation of the release and uptake of Glu in producing this toxic concentration has not been adequately ascertained. The authors report that in hippocampal slices, the output of Glu significantly increased under in vitro ischemic states. Glu in the extracellular space increased fivefold. Since daurisoline, a drug that blocks N-type Ca2+ channels, or Ca(2+)-free solution potently and effectively lowered this stimulated output, it was hypothesized that the Glu output is mediated by Ca2+ influx in nerve terminals. When the slices were incubated for 30 minutes under ischemic state, daurisoline caused only small alterations in the postischemic accumulation of Glu. However, Glu accumulation was markedly attenuated by H-7, but not by calmidazolium, facilitated by PDB whereas 8-bromo-cAMP was without effect. It appears therefore that during a 30-minute ischemic insult, protein kinase C (PKC) was involved in the Glu accumulation of supernatant. A direct demonstration of this concept was obtained by showing significant increases in PKC activation in presynaptic nerve terminals (from 1.34 +/- 0.1 to 9.34 +/- 0.89 U) following 30 minutes of ischemia. DNQX, a non-NMDA receptor antagonist, potently reduced PKC activities and decreased extra Glu accumulation. Also observed was the inhibition of 1-[3H]-Glu uptake into synaptosomes by PDB. These results provide direct evidence that Ca2+ influx enhances Glu release, which in turn leads to inhibition of its reuptake, and is coupled with PKC activities in presynaptic nerve terminals.
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PMID:Accumulation of glutamate is regulated by calcium and protein kinase C in rat hippocampal slices exposed to ischemic states. 810 81

Myocardial protection in the rabbit induced by ischemic preconditioning is thought to be adenosine receptor linked, but the signaling pathway responsible for the protection has yet to be identified. This study tests whether protein kinase C could be involved. Either of two inhibitors of protein kinase C, staurosporine (50 micrograms/kg) or polymyxin B (24 mg/kg), were administered to rabbits subjected to 30 min regional myocardial ischemia followed by 180 min reperfusion. Half of the rabbits were preconditioned while the other half served as nonpreconditioned controls. Nonpreconditioned hearts without drug or treated with staurosporine or polymyxin B resulted in 37.8 +/- 3.1, 40.5 +/- 2.8, and 42.0 +/- 7.0% infarction of the risk zone, respectively. Preconditioning limited infarct size to 7.3 +/- 2.7%. Both inhibitors blocked protection in preconditioned hearts with 36.2 +/- 2.7 and 40.9 +/- 2.5% of the risk zone infarcted, respectively. Activation of protein kinase C with 4 beta-phorbol 12-myristate 13-acetate (PMA) or with 1-oleyl-2-acetyl glycerol (OAG) mimicked preconditioning in buffer-perfused hearts. PMA (0.01 nmol/min) or OAG (10 nmol/min) for 5 min was followed by 10 min of washout. Infarct size after 30 min regional ischemia was limited in the PMA and OAG groups (6.4 +/- 1.4 and 11.7 +/- 3.3 vs. 28.0 +/- 4.5% in untreated controls) and was equipotent with ischemic preconditioning (11.8 +/- 2.2%). Polymyxin B also blocked protection from ischemic preconditioning in the isolated heart (33.0 +/- 5.0%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preconditioning protects ischemic rabbit heart by protein kinase C activation. 816 Aug 17

Atrial natriuretic peptide (ANP) is released from the myocardium after the activation of protein kinase C and/or ischemia, events that are associated with an increase in platelet activating factor (PAF) production in this tissue. In this study we demonstrate that PAF, but not lyso-PAF, induces a concentration-dependent increase in ANP secretion in spontaneously beating neonatal rat cardiomyocytes, a response associated with increases in cellular adenosine 3',5'-cyclic monophosphate (cAMP) formation, calcium influx, and the mobilization of calcium from intracellular stores. cAMP formation and calcium influx appear to play major roles in PAF-induced ANP secretion in this system, insofar as PAF-induced ANP release was substantially reduced in the presence of the (R)-p-diastereoisomer of adenosine 3',5'-cyclic monophosphorothioate (10 microM), whereas both PAF-induced calcium influx and ANP secretion were abolished in the presence of the calcium channel antagonist nifedipine (0.1 microM). Consistent with these results, N6-2'-O-dibutyryl cAMP (DBcAMP, 10 microM) and/or forskolin (0.1 microM) simultaneously increased cAMP production, calcium influx, and ANP release in these cells, with both DBcAMP- and forskolin-induced ANP secretion being fully abolished in the presence of 0.1 microM nifedipine. Taken together, these results suggest that PAF, DBcAMP, and forskolin promote ANP secretion in spontaneously beating cardiomyocytes via the activation of a cAMP-dependent, nifedipine-sensitive myocardial calcium channel and that calcium influx is a major requirement for cAMP-induced ANP secretion in this system.
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PMID:Calcium influx in platelet activating factor-induced atrial natriuretic peptide release in rat cardiomyocytes. 816 60

To investigate the role of Ca(2+)-independent forms of protein kinase C (PKC) in ischemic neuronal injury, mRNA expression of PKC was studied by Northern blot analysis. Ischemia was produced in gerbils by 10-min bilateral carotid artery occlusion and was followed by recirculation for 15 min, 6 h, and 24 h. Brains of postischemic and sham-operated animals were removed, forebrains fresh frozen, and processed for Northern blot analysis. Three synthetic oligonucleotide probes based on published cDNA sequences of rat brain PKC for the isozymes delta, epsilon, and zeta were utilized for hybridization. Northern blot analysis showed increased hybridization signal for all three PKC isozymes examined in the 6- and 24-h postischemic groups. Of these, the twofold increases in the expression of PKC delta and zeta were statistically significant in comparison to the control. These results suggest that the mRNA levels of Ca(2+)-independent forms of PKC, in particular, delta and zeta, are temporally stimulated by ischemic injury in the brain and may imply an important role of the enzyme in postischemic neuronal damage. However, since the protein itself was not examined in this study, the significance of the increased expression cannot be ascertained. However, it may reflect a compensatory response to the loss of PKC reported to occur in the reperfusion phase.
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PMID:mRNA levels of Ca(2+)-independent forms of protein kinase C in postischemic gerbil brain by northern blot analysis. 817 68

Multiple processes lead to neuronal death after ischemia, but the generation of nitric oxide (NO) is a key component in this cascade of events. The mechanisms that regulate the extent of neuronal degeneration during anoxia and NO toxicity are multifactorial. Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP-dependent protein kinase (PKA), and the calcium/calmodulin-dependent protein kinase II (CaM-II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM-II, and cGMP-dependent protein kinase modified the toxic effects of anoxia and NO. Down-regulation of PKC activity with PMA (1 microM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity (H-7, H-8, sphingosine, and staurosporine) also were neuroprotective. Down-regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N omega-methyl-L-arginine. Thus, although down-regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP-dependent protein kinase activity, but not the activity of the CaM-II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP-dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP-dependent protein kinase activity but is not dependent on the CaM-II pathway. Understanding the involvement of PKC, PKA, and the cGMP-dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease.
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PMID:Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. 823 Mar 23

Mechanisms of Mn-superoxide dismutase (Mn-SOD) expression in human umbilical endothelial cells were investigated by Northern blot analysis, enzyme-linked immunosorbent assay, and immunoelectron microscopy. The Mn-SOD in human endothelial cells was markedly induced by the cytokines tumor necrosis factor (TNF), interleukin-1, and lipopolysaccharide as well as by phorbol esters [12-O-tetradecanoylphorbol 13-acetate (TPA)]. The induction was partially blocked by dexamethasone and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, a potent inhibitor of protein kinase C (PKC). In endothelial cells in which PKC had been desensitized to TPA by pretreatment for 24 h, addition of TNF caused overexpression of Mn-SOD. These facts suggested that at least two separate signal-transducing pathways are involved in expression of the Mn-SOD gene. Immunoelectron-microscopic studies showed that Mn-SOD was localized to the mitochondrial matrix of the capillary vascular endothelial cells of cardiac tissues and cultured endothelial cells. Mn-SOD, which is normally abundant in endothelial cells relative to other cell types, may play an important protective role against stresses such as ischemia and inflammation.
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PMID:Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction. 823 2

In the model of transient brain ischemia of 6-min duration in gerbils we have estimated: 1. The concentration of brain gangliosides: A significant decrease to about 70% of control was observed selectively in the hippocampus at 3 and 7 d after ischemia. 2. The activity of Na+,K(+)-ATPase: The enzyme activity was not affected in either hippocampus nor in cerebral cortex. 3. The malonaldehyde (MDA) concentration: The levels of MDA had increased at 30 min after ischemia up to 123 and 129% of control in hippocampus and cerebral cortex, respectively. 4. Immunoreactivity of protein kinase C detected by Western blotting: In hippocampus the early translocation toward membranes was followed by a decrease in total enzyme content at 6, 24, 72, and 96 h of postischemic recovery. Also, a sharp increase of 50 kDa isoform (PKM) was noticed immediately and at the early recovery times. The behavior of these biochemical markers of ischemic brain injury in the hippocampus after the short (6 min) insult was contrasted with their reaction in the cerebral cortex as well as after prolongation of the ischemia to 15 min. These results taken together indicate that an early increase in PKC translocation followed by a decrease is the most symptomatic for selective, delayed, postischemic hippocampal injury, resulting from short duration (6 min) ischemia of the gerbil brain.
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PMID:Protein kinase C as an early and sensitive marker of ischemia-induced progressive neuronal damage in gerbil hippocampus. 829 17

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