UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor nuclear factor kappaB (NF-kappaB) regulates multiple immediate-early gene expressions involved in immune and inflammatory responses and cellular defenses. Ischemia-reperfusion induces many immediate-early gene expressions, but little is known about the NF-kappaB activation in myocardium during ischemia and reperfusion. This study demonstrated that ischemia alone rapidly induced NF-kappaB activation in the myocardium of isolated working rat hearts. Electrophoretic mobility shift assay showed that NF-kappaB binding activity significantly increased in the nucleus after 5 min of ischemia and remained elevated for up to 30 min. Western blot analysis suggested that the levels of inhibitory IkappaBalpha protein in the cytoplasm became markedly decreased at 4, 5, 7.5, and 10 min of ischemia but were gradually restored following 10 min of ischemia. Reduction of IkappaBalpha protein in the cytoplasm by ischemia resulted in NF-kappaB translocation to the nucleus. Northern blot hybridization showed that IkappaBalpha mRNA levels were not significantly elevated during myocardial ischemia. Pyrrolidine dithiocarbamate, an antioxidant, significantly inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus. Reperfusion following short periods of ischemia augmented NF-kappaB binding activity in the nucleus induced by ischemia. The results suggest that early activation of NF-kappaB induced by ischemia in the myocardium could be a signal mechanism for controlling and regulating immediate-early gene expression during ischemia-reperfusion.
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PMID:Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. 995 Aug 56

Endothelial cell death may contribute to tissue injury from ischemia. Little is known, however, about the characteristics of endothelial cell death in response to hypoxia. Using an in vitro model, we found that human umbilical vein endothelial cells were resistant to hypoxia-induced cell death with only a 2% reduction in viability at 24 h and 45% reduction in viability at 48 h. Overexpression of a mutant, IkappaBalpha, via adenoviral vector did not potentiate cell death in hypoxia, indicating that nuclear factor-kappaB activation was not involved in cytoprotection. Cell death in hypoxia was determined to be apoptotic by 3' labeling of DNA using terminal deoxynucleotidyl transferase staining and reversibility of cell death with a caspase inhibitor. Exposure of endothelial cells to hypoxia did not alter levels of proapoptotic and antiapoptotic Bcl-2 family members Bax and Bcl-XL by immunoblot analysis. In contrast, changes in p53 protein levels correlated with the induction of apoptosis in hypoxic endothelial cells. Inhibition of the proteasome increased p53 protein levels and accelerated cell death in hypoxia. Overexpression of p53 by adenoviral transduction was sufficient to initiate apoptosis of normoxic endothelial cells. These data provide a framework for the study of factors regulating endothelial cell survival and death in hypoxia.
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PMID:Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. 1007 3

Ischemia/reperfusion contributes to the hepatic injury in resection and transplantation of the liver. However, the precise mechanisms involved in hypoxia stress remain to be clarified. Pro-inflammatory cytokines including interleukin 1beta (IL-1beta) induce a gene expression of inducible nitric oxide synthase (iNOS) and produce nitric oxide, which exerts either a cytoprotective or toxic effect. In this report, we found that hypoxia and heat markedly inhibited the induction of nitric oxide production stimulated by IL-1beta in rat cultured hepatocytes. Both treatments also abolished the induction of iNOS protein and mRNA. However, hypoxia could not prevent either degradation of an inhibitory protein (IkappaBalpha) of nuclear factor-kappaB (NF-kappaB) or translocation of NF-kappaB to the nucleus, whereas heat inhibited both of the IkappaBalpha degradation and NF-kappaB translocation. Transfection experiments with iNOS promoter construct revealed that hypoxia as well as heat significantly inhibited the transactivation of iNOS gene. Further, a hypoxia-response element located in the promoter was not involved in the inhibition of iNOS induction by hypoxia. These results indicate that hypoxia and heat suppress iNOS gene induction at the transcriptional level through different mechanisms. Reduction of nitric oxide production under hypoxic conditions may be implicated in the cellular damage or protection during hepatic ischemia/reperfusion.
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PMID:Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes. 1105 54

Recombinant adeno-associated virus (rAAV) transduction is limited in vivo, yet can be enhanced by hydroxyurea, ultraviolet-irradiation, or adenovirus coinfection, possibly via mechanisms involving stress in the host cell. Because chronic ethanol induces oxidative stress, it was hypothesized that chronic ethanol would increase rAAV transduction in vivo. To test this hypothesis, rAAV encoding beta-galactosidase was given to Wistar rats that later received either ethanol diet or high-fat control diet via an enteral-feeding protocol for 3 weeks. Expression and activity of beta-galactosidase in the liver were increased nearly 5-fold by ethanol. The increase in transgene expression was inhibited by antioxidant diphenylene iodonium (DPI), which is consistent with the hypothesis that ethanol causes an increase in rAAV transduction via oxidative stress. Ethanol increased DNA synthesis only slightly; however, it increased the nuclear transcription factor kappaB (NFkappaB) 4-fold, a phenomenon also sensitive to DPI. Moreover, a 6-fold increase in rAAV transgene expression was observed in an acute ischemia-reperfusion model of oxidative stress. Transgene expression was transiently increased 24 hours after ischemia-reperfusion 3 days and 3 weeks after rAAV infection. Further, adenoviral expression of superoxide dismutase or IkappaBalpha superrepressor inhibited rAAV transgene expression caused by ischemia-reperfusion. Therefore, it is concluded that ethanol increases rAAV transgene expression via mechanisms dependent on oxidative stress, and NFkappaB likely through enhancement of cytomegaloviral (CMV) promoter elements. Alcoholic liver disease is an attractive target for gene therapy because consumption of ethanol could theoretically increase expression of therapeutic genes (e.g., superoxide dismutase). Moreover, this study has important implications for rAAV gene therapy and potential enhancement and regulation of transgene expression in liver.
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PMID:Chronic ethanol increases adeno-associated viral transgene expression in rat liver via oxidant and NFkappaB-dependent mechanisms. 1105 56

There is limited evidence that inhibition of the activity of the cytosolic cysteine protease calpain reduces ischemia/reperfusion injury. The multiple organ injury associated with hemorrhagic shock is due at least in part to ischemia (during hemorrhage) and reperfusion (during resuscitation) of target organs. Here we investigate the effects of calpain inhibitor I on the organ injury (kidney, liver, pancreas, lung, intestine) and dysfunction (kidney) associated with hemorrhagic shock in the anesthetized rat. Hemorrhage and resuscitation with shed blood resulted in an increase in calpain activity (heart), activation of NF-kappaB (kidney), expression of iNOS and COX-2 (kidney), and the development of multiple organ injury and dysfunction, all of which were attenuated by calpain inhibitor I (10 mg/kg i.p.), administered 30 min prior to hemorrhage. Chymostatin, a serine protease inhibitor that does not prevent the activation of NF-kappaB, had no effect on the organ injury/failure caused by hemorrhagic shock. Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon. Selective inhibition of iNOS activity with L-NIL reduced the circulatory failure and liver injury, while selective inhibition of COX-2 activity with SC58635 reduced the renal dysfunction and liver injury caused by hemorrhagic shock. Thus, we provide evidence that the mechanisms by which calpain inhibitor I reduces the circulatory failure as well as the organ injury and dysfunction in hemorrhagic shock include 1) inhibition of calpain activity, 2) inhibition of the activation of NF-kappaB and thus prevention of the expression of NFkappaB-dependent genes, 3) prevention of the expression of iNOS, and 4) prevention of the expression of COX-2. Inhibition of calpain activity may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
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PMID:Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. 1114 5

We have demonstrated that in vitro brief ischemia activates nuclear factor (NF)-kappaB in rat myocardium. We report in vivo ischemia-reperfusion (I/R)-induced NF-kappaB activation, IkappaB kinase -beta (IKKbeta) activity, and IkappaBalpha phosphorylation and degradation in rat myocardium. Rat hearts were subjected to occlusion of the coronary artery for up to 45 min or occlusion for 15 min followed by reperfusion for up to 3 h. Cytoplasmic and nuclear proteins were isolated from ischemic and nonischemic areas of each heart. NF-kappaB activation was increased in the ischemic area (680%) after 10 min of ischemia and in the nonischemic area (350%) after 15 min of ischemia and remained elevated during prolonged ischemia and reperfusion. IKKbeta activity was markedly increased in ischemic (1,800%) and nonischemic (860%) areas, and phosphorylated IkappaBalpha levels were significantly elevated in ischemic (180%) and nonischemic (280%) areas at 5 min of ischemia and further increased after reperfusion. IkappaBalpha levels were decreased in the ischemic (45%) and nonischemic (36%) areas after 10 min of ischemia and remained low in the ischemic area during prolonged ischemia and reperfusion. The results suggest that in vivo I/R rapidly induces IKKbeta activity and increases IkappaBalpha phosphorylation and degradation, resulting in NF-kappaB activation in the myocardium.
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PMID:Early activation of IKKbeta during in vivo myocardial ischemia. 1117 72

Cellular redox state has been increasingly recognized as a critical component of stress-induced cellular responses and disease. Inherent in these responses are reactive oxygen species (ROS), which inflict direct cellular damage in addition to acting as intracellular second messengers modulating signal transduction pathways. These intracellular highways of communication are critical in determining cell fates and whole-organ responses following environmental injury. Although gene therapy for inherited and acquired disorders has exploded in the last decade, the application of gene therapeutic approaches for transient pathologic conditions resulting from environmental stress is just beginning to be recognized. This review will summarize the theoretical and practical applications of gene therapy for the treatment of environmental injury by modulating redox-activated cellular responses. Several approaches can be utilized to achieve this goal. These include the application of gene targeting to modulate the cellular redox state directly by expressing recombinant genes capable of degrading ROS at pathophysiologic important subcellular sites. The use of mitochondrial superoxide dismutase (MnSOD), which degrades superoxides arising from ischemia/reperfusion injury, is one example of this approach. MnSOD serves as a "garbage disposal" for potentially toxic ROS prior to cellular injury and the activation of signal transduction cascades important in whole-organ pathology and inflammation. In contrast, some ROS have been suggested to have beneficial effects on cellular responses following environmental injury. Hence, expressing the nitrogen oxygen synthetase gene (NOS) to enhance the levels of nitric oxide (NO.) and augment the beneficial effects of this compound has also been suggested as a useful redox-modulating gene therapy approach. Lastly, indirect intervention in signal transduction pathways following environmental stress by expressing dominant inhibitory proteins of redox-activated signal transduction cascades has also been useful in modulating cellular responses to redox stress. Two such examples have utilized dominant inhibitory forms of the retinoblastoma gene product (Rb) and IkappaBalpha which prevent activation of cyclin-dependent protein kinases and NF-kappaB, respectively. Ultimately, the most efficacious therapeutic approach or combination of approaches that alter the redox responsiveness of cells and organs to environmental injury will be determined through a comprehensive understanding of the relevant pathophysiologic processes.
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PMID:Redox-mediated gene therapies for environmental injury: approaches and concepts. 1122 32

The transcription factor nuclear factor-kappaB (NFkappaB) is an ubiquitously expressed inducible regulator of a broad range of genes and plays a pivotal role in cell death and survival pathways. Three models of brain tolerance (ischemic, epileptic, and polyunsaturated fatty acid-induced preconditioning), known to confer resistance to neurons against ischemia or status epilepticus, were used to determine whether NFkappaB mediated the late preconditioning. A sublethal 3 min ischemia, a dose of 5 mg/kg kainic acid (KA5) or 500 nmol of linolenic acid (LIN500) led to a rapid increase of NFkappaB DNA-binding activity and nuclear translocation of p65 and p50 subunits of NFkappaB in neurons. Pretreatment with the NFkappaB inhibitor diethyldithiocarbamate or kappaB decoy DNA blocked the increased DNA-binding activity and the nuclear translocation of NFkappaB and abolished the neuroprotective effects of different delayed preconditionings against severe ischemia or epilepsy. The inhibition of NFkappaB observed in rats preconditioned with 3 min ischemia, KA5 or LIN500 treatments compared with ischemic or epileptic controls was correlated with the prevention of the inducible degradation of the inhibitory protein IkappaBalpha. Preconditioning probably inhibits the activation of NFkappaB by interfering with a pathway that leads to the direct transcriptional activation of IkappaBalpha by NFkappaB itself. The present work provides evidence that activation of NFkappaB is a crucial step in the signal transduction pathway that underlies the development of brain tolerance and may open new strategies in the prevention of cerebral diseases, such as ischemia or epilepsy.
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PMID:Activation of the nuclear factor-kappaB is a key event in brain tolerance. 1142 94

A brief period of hepatic ischemia protects the liver against subsequent ischemia-reperfusion (IR) injury, but the mechanism of such preconditioning is poorly understood. We examined whether preconditioning activated nuclear factor kappa B (NF-kappaB), the stress-activated protein kinases (SAPK), c-Jun N-terminal kinase-1 (JNK-1) and p38, and entry into the cell cycle. We used a murine model of partial hepatic ischemia. Preconditioning was performed by clamping the vasculature for 2 to 20 minutes, and allowing reperfusion for 10 minutes before 90-minute ischemia or IR. As assessed by serum alanine aminotransferase (ALT) levels and liver histology, preconditioning periods of 5 and 10 minutes were highly protective against IR injury, whereas 2-, 15-, and 20-minute intervals were ineffective. Preconditioning was associated with entry of hepatocytes into the cell cycle within 2 hours of subsequent IR, as indicated by proliferating cell nuclear antigen (PCNA) nuclear staining, induction of cyclin D1 and numerous mitotic figures; in the absence of preconditioning, such changes were not seen until 24 hours. Preconditioning increased nuclear binding of NF-kappaB within 30 minutes of the subsequent ischemic interval, paralleled by degradation of inhibitory (binding) protein for NF-kappaB (IkappaBalpha). Ischemic preconditioning also activated p38 kinase and JNK-1, which are known to converge on cyclin D1 regulation. The protective effect of the preconditioning regimen was more closely associated with p38 kinase than JNK-1 activation. In conclusion, the hepatoprotective effects of ischemic preconditioning are associated with activation of NF-kappaB and SAPKs that are associated with entry of hepatocytes into the cell cycle, a critical biological effect that favors survival of the liver against ischemic and IR injury.
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PMID:Hepatic ischemic preconditioning in mice is associated with activation of NF-kappaB, p38 kinase, and cell cycle entry. 1208 53

The transcription factor NFkappaB is a critical immediate early response gene involved in modulating cellular responses and apoptosis following diverse environmental injuries. The activation of NFkappaB is widely accepted to play an anti-apoptotic role in cellular responses to injury. Hence, enhancing NFkappaB activation in the setting of injury has been proposed as one potential therapeutic approach to environmental injuries. To this end, we constructed a recombinant adenoviral vector (Ad.IkappaBalphaAS) expressing antisense IkappaBalpha mRNA that is capable of augmenting NFkappaB activation prior to and following four types of cellular injury [TNF-alpha, UV, hypoxia/reoxygenation (H/R) or pervanadate treatment]. Biochemical and functional analyses of NFkappaB activation pathways for these injuries demonstrated two categories involving either serine (S32/36) phosphorylation (TNF-alpha, UV) or tyrosine (Y42) phosphorylation (H/R or PV) of IkappaBalpha. We hypothesized that activation of NFkappaB prior to injury using antisense IkappaBalpha mRNA would reduce apoptosis. As anticipated, recombinant adenoviral IkappaBalpha phosphorylation mutants (Ad.IkappaBalphaS32/36A or Ad.IkappaBalphaY42F) preferentially reduced NFkappaB activation and enhanced apoptosis following injuries associated with either serine or tyrosine phosphorylation of IkappaBalpha, respectively. These studies demonstrate for the first time that an IkappaBalphaY42F mutant can effectively modulate NFkappaB-mediated apoptosis in an injury-context-dependent manner. Interestingly, constitutive activation of NFkappaB following Ad.IkappaBalphaAS infection reduced apoptosis only following injuries associated with IkappaBalpha Y42, but not S32/36, phosphorylation. These findings demonstrate that the temporal regulation of NFkappaB and the apoptotic consequences of this activation are differentially influenced by the pathway mediating NFkappaB activation. They also provide new insight into the therapeutic potential and limitations of modulating NFkappaB for environmental injuries such as ischemia/reperfusion and pro-inflammatory diseases.
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PMID:Temporal pattern of NFkappaB activation influences apoptotic cell fate in a stimuli-dependent fashion. 1243 72

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