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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine thought to play a major role in recruiting monocytes to the atherosclerotic plaque. Tissue factor (TF), the initiator of coagulation, is found in the atherosclerotic plaque, macrophages, and human aortic smooth muscle cells (SMC). The exposure of TF during plaque rupture likely induces acute thrombosis, leading to myocardial infarction and stroke. This report demonstrates that MCP-1 induces the accumulation of TF mRNA and protein in SMC and in THP-1 myelomonocytic leukemia cells. MCP-1 also induces TF activity on the surface of human SMC. The induction of TF by MCP-1 in SMC is inhibited by pertussis toxin, suggesting that the SMC MCP-1 receptor is coupled to a Gi-protein. Chelation of intracellular calcium and inhibition of protein kinase C block the induction of TF by MCP-1, suggesting that in SMC it is mediated by activation of phospholipase C. SMC bind MCP-1 with a Kd similar to that previously reported for macrophages. However, mRNA encoding the macrophage MCP-1 receptors, CCR2A and B, is not present in SMC, indicating that they possess a distinct MCP-1 receptor. These data suggest that in addition to being a chemoattractant, MCP-1 may have a procoagulant function and raise the possibility of an autocrine pathway in which MCP-1, secreted by SMC and macrophages, induces TF activity in these same cells.
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PMID:Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells. 935 21

Chronic exposure of cultured canine cerebral vascular smooth muscle cells to ethanol (10-400 mM) for 1-5 days resulted in significant concentration-dependent elevation in resting intracellular free calcium ([Ca2+]i) levels. Preincubation of these cultured vascular cells with inhibitors of protein kinase C (PKC), staurosporine and H7, induced no apparent changes from the control resting levels of [Ca2+]i. However, the increases of [Ca2+]i due to ethanol treatment were attenuated markedly by staurosporine and H7. Our data suggest that activation of PKC plays an important role in ethanol's action in producing a sustained rise in [Ca2+]i in cerebral vascular smooth muscle cells. Activation of PKC could thus play a crucial role in the pathogenesis of alcohol-induced cerebral ischemia and stroke.
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PMID:Staurosporine and H7 attenuate ethanol-induced elevation in [Ca2+]i in cultured canine cerebral vascular smooth muscle cells. 950 40

We examined the expression of protein kinase C isoforms in infarcted tissue, penumbra and contralateral brain tissue from 10 patients who died between 1-52 days after ischaemic stroke. Ten patients aged 61-89 years were used in the study. Tissue samples were assayed for protein kinase C activity using a non-radioactive method, and specific isoforms expression determined by Western blotting and staining with anti-PKC polyclonal antibodies. There was a 2-24 fold increase in PKC gamma in the ischaemic penumbra of nine out of 10 patients compared to contralateral tissue. In infarcted tissue expression of PKC gamma was not significantly changed in any of 10 samples but the beta I isoform increased in eight and the beta II in nine patients. There was no significant change in expression in PKC alpha or in infarct or penumbra. Differences in total PKC activity were not specific in seven out of eight patients and it is difficult to estimate their significance. In conclusion after ischaemia there was an altered expression of PKC isoforms with an increase of PKC gamma in the surviving penumbra and beta I and beta II in the infarcted core.
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PMID:Protein kinase C expression and activity in the human brain after ischaemic stroke. 958 83

Oxidative stress is implicated in a number of neurological disorders including stroke, Parkinson's disease, and Alzheimer's disease. To study the effects of oxidative stress on neuronal cells, we have used an immortalized mouse hippocampal cell line (HT-22) that is particularly sensitive to glutamate. In these cells, glutamate competes for cystine uptake, leading to a reduction in glutathione and, ultimately, cell death. As it has been reported that protein kinase C activation inhibits glutamate toxicity in these cells and is also associated with the inhibition of apoptosis in other cell types, we asked if glutamate toxicity was via apoptosis. Morphologically, glutamate-treated cells underwent plasma membrane blebbing and cell shrinkage, but no DNA fragmentation was observed. At the ultrastructural level, there was damage to mitochondria and other organelles although the nuclei remained intact. Protein and RNA synthesis inhibitors as well as certain protease inhibitors protected the cells from glutamate toxicity. Both the macromolecular synthesis inhibitors and the protease inhibitors had to be added relatively soon after the addition of glutamate, suggesting that protein synthesis and protease activation are early and distinct steps in the cell death pathway. Thus, the oxidative stress brought about by treatment with glutamate initiates a series of events that lead to a form of cell death distinct from either necrosis or apoptosis.
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PMID:Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells. 964 55

Oxidative stress may be an important factor in several pathological brain conditions. A contributing factor in many such conditions is excessive glutamate release, and subsequent glutamatergic neuronal stimulation, that causes increased production of reactive oxygen species (ROS), oxidative stress, excitotoxicity and neuronal damage. Glutamate release is also associated with illnesses such as Alzheimer's disease, stroke, and brain injury. Glutamate may interact with an environmental toxin, lead, and this interaction may result in neuronal damage. Glutamate-induced ROS production is greatly amplified by lead in cultured neuronal cells. Alterations in protein kinase C (PKC) activity seem to be important both for glutamate-induced ROS production, and for the amplification of glutamate-induced ROS production by lead. It is possible that the neurotoxic effects of lead are amplified through glutamate-induced neuronal excitation. Cholinergic stimulation can also trigger ROS production in neuronal cells. PKC seems to play a key-role also in cholinergic-induced ROS production superoxide anion being the primary reactive oxygen species. There seems to be a close relationship between the responses of cholinergic muscarinic and glutamatergic receptors because glutamate receptor antagonists inhibit cholinergic-induced activation of human neuroblastoma cells. Glutamatergic neuronal stimulation may be a common final pathway in several brain conditions in which oxidative stress and ensuing excitotoxicity plays a role.
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PMID:Glutamate-stimulated ROS production in neuronal cultures: interactions with lead and the cholinergic system. 974 27

BACKGROUND AND PURPOSE--Endothelin-1, in concentrations similar to that present in cerebrospinal fluid after fluid percussion brain injury (FPI), increases superoxide anion (O2-) production. Endothelin-1 also contributes to altered cerebral hemodynamics after FPI through impairment of ATP-sensitive K+ (KATP) channel function through protein kinase C (PKC) activation. Generation of O2- additionally occurs after FPI. Nitric oxide and cGMP elicit pial artery dilation through KATP channel activation. The present study was designed to determine whether PKC activation generates O2-, which, in turn, could link such activation to impaired KATP channel function after FPI. METHODS--Injury of moderate severity (1.9 to 2.1 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation. RESULTS--Phorbol 12, 13-dibutyrate (10(-6) mol/L), a PKC activator, increased superoxide dismutase-inhibitable NBT reduction from 1+/-1 to 37+/-5 pmol/mm2. Staurosporine (10(-7) mol/L), a PKC antagonist, blocked the NBT reduction after phorbol 12,13-dibutyrate and blunted the NBT reduction observed after FPI (1+/-1 to 15+/-2 versus 1+/-1 to 5+/-1 pmol/mm2 after FPI in the absence versus presence of staurosporine). Exposure of the cerebral cortex to a xanthine oxidase O2--generating system increased NBT reduction in a manner similar to FPI and blunted pial artery dilation to the KATP channel agonists cromakalim and calcitonin gene-related peptide, the nitric oxide releasers sodium nitroprusside and S-nitroso-N-acetylpenicillamine, and the cGMP analogue 8-bromo-cGMP (10+/-1% and 21+/-1% versus 4+/-1% and 9+/-1% for 10(-8) and 10(-6) mol/L cromakalim before and after activated oxygen-generating system exposure). CONCLUSIONS--These data show that PKC activation increases O2- production and contributes to such production observed after FPI. These data also show that an activated system that generates an amount of O2- similar to that observed with FPI blunted pial artery dilation to KATP channel agonists and nitric oxide/cGMP. These data suggest, therefore, that O2- generation links PKC activation to impaired KATP channel function after FPI.
Stroke 1999 Jan
PMID:Superoxide generation links protein kinase C activation to impaired ATP-sensitive K+ channel function after brain injury. 988 Apr 4

We have previously demonstrated that endothelin-1 (Et-1) induces human central nervous system-derived endothelial cells (CNS-EC) to produce and secrete the chemokine interleukin 8 (IL-8). In the present study, we use specific inhibitors and activators to elucidate the signal transduction pathways involved in this process. Et-1-induced IL-8 production was blocked by ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788, demonstrating that CNS-EC activation is initiated by Et-1 binding to the ET(A) receptor. IL-8 mRNA expression is blocked by the protein kinase C inhibitor bisindolylmaleimide or protein tyrosine kinase inhibitors, genestein and geldanamycin, establishing the involvement of the protein kinase C and protein tyrosine kinase pathways in the activation process. The transcription factor, NF-kappaB, is involved in Et-1 activation as determined by specific inhibitors of translocation and direct analysis of DNA-binding proteins. Neither inhibition nor activation of cAMP-dependent protein kinase affected IL-8 production in the absence or presence of Et-1. Similarly, no effect was observed upon inhibition of protein phosphatases by okadaic acid. Thus, the signal transduction process induced by Et-1 in CNS-EC, leading to increased mRNA IL-8 expression, is initiated by Et-1 binding to ET(A) receptor followed by subsequent activation of protein kinase C, protein tyrosine kinase, and NF-kappaB. Because increased expression of Et-1 is associated with hypertension and stroke and IL-8 is likely to be involved in the accumulation of neutrophils causing tissue damage in ischemic/reperfusion injury, identification of the mechanism involved in the Et-1-induced increase in IL-8 production may have significant therapeutic value.
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PMID:Endothelin-1-induced interleukin-8 production in human brain-derived endothelial cells is mediated by the protein kinase C and protein tyrosine kinase pathways. 1043 17

Bradykinin, a mediator of inflammation, is produced in the brain during trauma and stroke. It is thought to open the blood-brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of bradykinin on the expression of interleukin-6 (IL-6), a putative modulator of the blood-brain barrier, in astrocytes. IL-6 gene transcription was evaluated by transient transfection of the human IL-6 promoter linked to the luciferase gene. In murine astrocytes, bradykinin stimulated IL-6 secretion and gene transcription. The effect of bradykinin was blocked by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinases, and by bisindolylmaleimide I, an inhibitor of protein kinase C, suggesting the involvement of these protein kinases. Mutations in the multiple response element and the binding site for nuclear factor-kappaB (NF-kappaB), but not in other known elements of the IL-6 promoter, interfered with induction of IL-6 transcription. The involvement of NF-kappaB was supported further by the finding that overexpression of nmIkappaB alpha, a stable inhibitor of NF-kappaB, inhibited the induction of IL-6 by bradykinin. Bradykinin activated NF-kappaB in primary astrocytes as shown by increased DNA binding of NF-kappaB. These data demonstrate that bradykinin stimulates IL-6 expression through activation of NF-kappaB, which may explain several inflammatory effects of bradykinin.
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PMID:Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappaB. 1050 Nov 90

Inducible nitric oxide synthase (iNOS) has been implicated as a mediator of cellular toxicity in a variety of neurodegenerative disorders. Nitric oxide, which is generated in high quantities following induction of iNOS, combines with other oxygen radicals to form highly reactive, death-inducing compounds. Given the frequency of neuronal death due to neurodegenerative diseases, cerebral trauma, and stroke, it is important to study the mechanisms of regulation of iNOS in the brain. We demonstrated previously that angiotensin II (Ang II) decreases the expression of iNOS produced by bacterial endotoxin or cytokines in cultured astroglia prepared from adult rat brain. Here, we have addressed the mechanisms by which Ang II negatively modulates iNOS. The inhibitory effects of Ang II on lipopolysaccharide-induced expression of iNOS mRNA and protein and nitrite accumulation were mimicked by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate. Down-regulation of PKC produced by long-term treatment of astroglia with phorbol 12-myristate 13-acetate abolished the inhibitory effect of Ang II on lipopolysaccharide-stimulated expression of iNOS mRNA and nitrite accumulation. Finally, the reduction of lipopolysaccharide-induced nitrite accumulation by Ang II was attenuated by the selective PKC inhibitor chelerythrine. Collectively, these data indicate a role for PKC in the inhibitory actions of Ang II on iNOS expression in cultured astroglia.
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PMID:Angiotensin II-induced decrease in expression of inducible nitric oxide synthase in rat astroglial cultures: role of protein kinase C. 1064 12

Protein phosphorylation and dephosphorylation mediated by protein kinases and protein phosphatases, respectively, represent essential steps in a variety of vital neuronal processes that could affect susceptibility to ischemic stroke. In this study, the role of the neuron-specific gamma isoform of protein kinase C (gammaPKC) in reversible focal ischemia was examined using mutant mice in which the gene for gammaPKC was knocked-out (gammaPKC-KO). A period of 150 minutes of unilateral middle cerebral artery and common carotid artery (MCA/CCA) occlusion followed by 21.5 hours of reperfusion resulted in significantly larger (P < 0.005) infarct volumes (n = 10; 31.1+/-4.2 mm3) in gammaPKC-KO than in wild-type (WT) animals (n = 12; 22.6+/-7.4 mm3). To control for possible differences related to genetic background, the authors analyzed Balb/cJ, C57BL/6J, and 129SVJ WT in the MCA/CCA model of focal ischemia. No significant differences in stroke volume were detected between these WT strains. Impaired substrate phosphorylation as a consequence of gammaPKC-KO might be corrected by inhibition of protein dephosphorylation. To test this possibility, gammaPKC-KO mice were treated with the protein phosphatase 2B (calcineurin) inhibitor, FK-506, before ischemia. FK-506 reduced (P < 0.008) the infarct volume in gammaPKC-KO mice (n = 7; 24.6+/-4.6 mm3), but at this dose in this model, had no effect on the infarct volume in WT mice (n = 7; 20.5+/-10.7 mm3). These results indicate that gammaPKC plays some neuroprotective role in reversible focal ischemia.
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PMID:Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia. 1069 72


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