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)

p38MAPK has been implicated in the regulation of proinflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia. Phosphorylated p38MAPK immunoreactivity was observed in microglia in regions adjacent to, but not in, the dying CA1 neurons. In contrast, neither c-Jun N-terminal kinase 1 nor p42/p44MAPK activity was altered after ischemia. These results provide the first evidence for localization of activated p38MAPK in the CNS and support a role for p38MAPK in the microglial response to stress.
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PMID:Activation of p38MAPK in microglia after ischemia. 952 96

To investigate the effect of the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) on cerebral ischemic injury, temporospatial alterations of active (diphosphorylated) ERK1/2 immunoreactivity in hippocampus was examined. Western blot showed that diphosphorylated ERK1/2 were decreased at 10 min of cerebral ischemia but increased rapidly (within 2 min) and transiently (within 4 h) during reperfusion. Immunohistochemistry showed that little diphosphorylated ERK1/2 immunoreactivity was seen in CA1 pyramidal cell bodies after ischemia, while strong immunoreactivity were seen in neuronal bodies in CA3/DG and in fiber systems in both CA1 and CA3 regions. Cerebral ventricular infusion of PD98059, a specific inhibitor of ERK kinase, completely prevented ERK1/2 activation after ischemia but had no effect on the survival of pyramidal cells in CA1 subfield. The results suggest that ERK1/2 activation in hippocampus after brain ischemia may not interfere with the postischemic cell death in CA1 region.
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PMID:Extracellular signal-regulated kinase 1/2 activation in hippocampus after cerebral ischemia may not interfere with postischemic cell death. 1136 53

Although protein kinase C (PKC) activation is required for endothelial cell (EC) growth, migration, adhesion, and vessel formation, the role of individual PKC isoenzymes in these events is not defined. Because PKCalpha has been previously linked with enhanced EC migration and response to angiogenic growth factors, we characterized a specific phosphorothioate-modified 21-mer antisense PKCalpha (AS-PKCalpha). AS-PKCalpha (500 nmol/L) prevented the expression of PKCalpha protein by 90% in human ECs and did not reduce the expression of any other PKC isoenzyme. AS-PKCalpha reduced human EC migration by 64% compared with its control oligonucleotide in a "scratch" wounding assay, and AS-PKCalpha reduced human EC adhesion to the extracellular matrix protein vitronectin by 18%. Phosphorylation of mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) induced by vascular endothelial growth factor was inhibited by 30% in human ECs transfected with AS-PKCalpha. Compared with control, AS-PKCalpha also reduced the number of EC tubes formed in a 3D type I collagen gel assay by 37.5%. Finally, using an osmotic minipump, we infused AS-PKCalpha into mice in which myocardial infarction was induced by coronary ligation and found that the oligonucleotide was primarily taken up by intramyocardial blood vessels. Compared with the results with control oligonucleotide, AS-PKCalpha oligonucleotide inhibited the number of anti-PKCalpha-stained blood vessels by 48% and reduced the total vessel number by 72% as well. In conclusion, the expression of PKCalpha is required for full EC migration, adhesion to vitronectin, vascular endothelial growth factor-induced extracellular signal-regulated kinase activation, and tube formation and is likely to be of importance in myocardial angiogenesis in vivo after ischemia.
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PMID:Inhibition of protein kinase Calpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo. 1190 26

Despite the characterization of neuroprotection by transforming growth factor-beta1 (TGF-beta1), the signaling pathway mediating its protective effect is unclear. Bad is a proapoptotic member of the Bcl-2 family and is inactivated on phosphorylation via mitogen-activated protein kinase (MAPK). This study attempted to address whether MAPK signaling and Bad phosphorylation were influenced by TGF-beta1 and, furthermore, whether these two events were involved in the antiapoptotic effect of TGF-beta1. We found a gradual activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and MAPK-activated protein kinase-1 (also called Rsk1) and a concomitant increase in Bad phosphorylation at Ser(112) in mouse brains after adenovirus-mediated TGF-beta1 transduction under nonischemic and ischemic conditions induced by transient middle cerebral artery occlusion. Consistent with these effects, the ischemia-induced increase in Bad protein level and caspase-3 activation were suppressed in TGF-beta1-transduced brain. Consequently, DNA fragmentation, ischemic lesions, and neurological deficiency were significantly reduced. In cultured rat hippocampal cells, TGF-beta1 inhibited the increase in Bad expression caused by staurosporine. TGF-beta1 concentration- and time-dependently activated Erk1/2 and Rsk1 accompanied by an increase in Bad phosphorylation. These effects were blocked by U0126, a mitogen-activated protein kinase/Erk kinase 1/2 inhibitor, suggesting an association between Bad phosphorylation and MAPK activation. Notably, U0126 and a Rsk1 inhibitor (Ro318220) abolished the neuroprotective activity of TGF-beta1 in staurosporine-induced apoptosis, indicating that activation of MAPK is necessary for the antiapoptotic effect of TGF-beta1 in cultured hippocampal cells. Together, we demonstrate that TGF-beta1 suppresses Bad expression under lesion conditions, increases Bad phosphorylation, and activates the MAPK/Erk pathway, which may contribute to its neuroprotective activity.
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PMID:Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. 1201 9

Adenosine is released from the myocardium, endothelial cells, and skeletal muscle in ischemia and is an important regulator of coronary blood flow. We have already shown that acute (2 min) activation of A2a purinoceptors stimulates NO production in human fetal umbilical vein endothelial cells (1) and now report a key role for p42/p44 mitogen-activated protein kinases (p42/p44MAPK) in the regulation of the l-arginine-nitric oxide (NO) signaling pathway. Expression of mRNA for the A2a-, A2b-, and A3-adenosine receptor subtypes was abundant whereas A1-adenosine receptor mRNA levels were negligible. Activation of A2a purinoceptors by adenosine (10 microM) or the A2a receptor agonist CGS21680 (100 nM) resulted in an increase in l-arginine transport and NO release that was not mediated by changes in intracellular Ca2+, pH, or cAMP. Stimulation of endothelial cells with adenosine was associated with a membrane hyperpolarization and phosphorylation of p42/p44MAPK. l-NAME abolished the adenosine-induced hyperpolarization and stimulation of l-arginine transport whereas sodium nitroprusside activated an outward potassium current. Genistein (10 microM) and PD98059 (10 microM), an inhibitor of MAPK kinase 1/2 (MEK1/2), inhibited adenosine-stimulated l-arginine transport, NO production, and phosphorylation of p42/p44MAPK. We found no evidence for activation of eNOS via the serine/threonine kinase Akt/PKB (protein kinase B) in adenosine-stimulated cells. Our results provide the first evidence that adenosine stimulates the endothelial cell l-arginine-NO pathway in a Ca2+-insensitive manner involving p42/p44MAPK, with release of NO leading to a membrane hyperpolarization and activation of l-arginine transport.
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PMID:Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. 1237 81

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:Transforming growth factor-beta and ischemic brain injury. 1451 14

Although clinical diabetes mellitus is obviously a high risk factor for myocardial infarction, there is disagreement about the sensitivity of ischemic injury of an infarcted myocardium in experimental studies. The present study evaluated the influences of different durations of hyperglycemia on ischemic and reperfusion injuries of the myocardium, and focused on extracellular signal-regulated kinase 1/2 (ERK1/2), which plays an important role in the intracellular signaling pathway and is reported to be associated with myocardial protection against heart injury. Short- and long-term hyperglycemias were induced in rats by streptozotocin (STZ) injection and the rats were examined 4 (4WDM) and 20 weeks (20WDM) after the treatment. Ischemia and reperfusion were induced by occlusion and reperfusion (I/R) of the left coronary artery (LCA). I/R-induced infarct size was determined using triphenyltetrazolium chloride (TTC) staining. After 20 weeks of STZ treatment (20WDM+I/R), the infarct size in the rat heart increased by 65.2 +/- 4.3%, whereas after 4 weeks of STZ treatment (4WDM+I/R), the infarct size decreased compared with the time-matched I/R group (43.1 +/- 3.6% and 59.5 +/- 5.6%, respectively). The number of dead myocytes including necrotic and apoptotic cells was determined using horseradish peroxidase (HRP) and terminal deoxynucleotide nick-end labeling (TUNEL) methods. The number of dead myocytes decreased in the 4WDM+I/R group, while the number of dead myocytes increased markedly in the 20WDM+I/R group, compared with the time-matched I/R group. The increment of ERK1/2 phosphorylation in the 4WDM group and the slight enhancement of this phosphorylation by I/R treatment were observed by western blotting. However, in the 20WDM group, the level of ERK1/2 phosphorylation reduced by approximately 1/3 compared with the time-matched control group; moreover, I/R treatment did not enhance the phosphorylation level. This study demonstrated that short- and long-term hyperglycemias exert opposite influences on ischemic myocardial injury, and these contradictory influences may depend on an ERK1/2-mediated intracellular signaling pathway.
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PMID:Contradictory effects of short- and long-term hyperglycemias on ischemic injury of myocardium via intracellular signaling pathway. 1473 70

Extracellular signal-regulated kinase 1/2 (ERK1/2) is known to function in cell survival in response to various stresses; however, the mechanism of cell survival by ERK1/2 remains poorly elucidated in ischemic heart. Here we applied functional proteomics by two-dimensional electrophoresis to identify a cellular target of ERK1/2 in response to ischemic hypoxia. Approximately 1500 spots were detected by Coomassie Brilliant Blue staining of a sample from unstimulated cells. The staining intensities of at least 50 spots increased at 6-h reoxygenation after 2-h ischemic hypoxia. Of the 50 spots that increased, at least 4 spots were inhibited in the presence of PD98059, a MEK inhibitor. A protein with a molecular mass of 52 kDa that is strongly induced by ERK1/2 activation in response to ischemic hypoxia and reoxygenation was identified as alpha-enolase, a rate-limiting enzyme in the glycolytic pathway, by liquid chromatography-mass spectrometry and amino acid sequencing. The expressions of the alpha-enolase mRNA and protein are inhibited during reoxygenation after ischemic hypoxia in the cells containing a dominant negative mutant of MEK1 and treated with a MEK inhibitor, PD98059, leading to a decrease in ATP levels. alpha-Enolase expression is also observed in rat heart subjected to ischemia-reperfusion. The induction of alpha-enolase by ERK1/2 appears to be mediated by c-Myc. The introduction of the alpha-enolase protein into the cells restores ATP levels and prevents cell death during ischemic hypoxia and reoxygenation in these cells. These results show that alpha-enolase expression by ERK1/2 participates in the production of ATP during reoxygenation after ischemic hypoxia, and a decrease in ATP induces apoptotic cell death. Furthermore, alpha-enolase improves the contractility of cardiomyocytes impaired by ischemic hypoxia. Our results reveal that ERK1/2 plays a role in the contractility of cardiomyocytes and cell survival through alpha-enolase expression during ischemic hypoxia and reoxygenation.
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PMID:ERK1/2 regulates intracellular ATP levels through alpha-enolase expression in cardiomyocytes exposed to ischemic hypoxia and reoxygenation. 1545 7

Toll-like receptor-4 (TLR4) and its signaling molecule interleukin-1 receptor-associated kinase (IRAK-1) play an important role in host defense and tissue inflammation. Intriguingly, systemic administration of lipopolysaccharide (LPS), the agonist for TLR4, confers a cardio-protective effect against ischemic injury. However, the mechanisms leading to the cardiac protection remain largely unknown. The present study was designed to investigate the role of TLR4 activation by LPS in protecting cardiomyocytes (CM) against apoptosis in an in vitro model of ischemia and to explore the downstream mechanisms leading to the protective effect. Incubation with LPS led to activation of IRAK-1 and protected CMs against serum deprivation (SD)-induced apoptosis as demonstrated by DNA laddering, histone-DNA fragment enzyme-linked immunosorbent assay, and activation of caspase-3. Phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase 1/2, and IkappaB kinase beta appear to contribute to the anti-apoptotic effect of LPS since the specific inhibitors, wortmannin, PD98059, and dominant negative IKKbeta transgene expression reversed the LPS effect. To assess whether LPS improves CM function, we examined intracellular Ca(2+) transients and cell shortening in single adult rat CMs. SD for 6 h dramatically inhibited Ca(2+) transients and CM contractility. LPS at 500 ng/ml significantly improved the [Ca(2+)](i) transients and enhanced contractility in control CMs as well as in CMs subjected to SD. Importantly, transient ischemia led to rapid activation of IRAK-1 in cultured CMs and in adult rat myocardium. Adenovirus-mediated transgene expression of IRAK-1 but not its kinase-deficient mutant IRAK-1(K239S) protected CMs against SD-induced apoptosis. Taken together, these data suggest an important role of TLR4 signaling via IRAK-1 in protecting against SD-induced apoptosis.
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PMID:Lipopolysaccharide improves cardiomyocyte survival and function after serum deprivation. 1579 10

Adrenomedullin (AM) is a potent, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and focal adhesion kinase in endothelial cells. Both AM and its receptor, calcitonin receptor-like receptor, are upregulated through a hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector, gelatin. Positively charged gelatin holds negatively charged plasmid DNA in its lattice structure. DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM DNA-gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb ischemia. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs. Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using gelatin may be applicable for intractable cardiovascular disease.
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PMID:Adrenomedullin: angiogenesis and gene therapy. 1588 52


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