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)

Reperfusion after global brain ischemia results initially in a widespread suppression of protein synthesis in neurons, which persists in vulnerable neurons, that is caused by the inhibition of translation initiation as a result of the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha). To identify kinases responsible for eIF2alpha phosphorylation [eIF2alpha(P)] during brain reperfusion, we induced ischemia by bilateral carotid artery occlusion followed by post-ischemic assessment of brain eIF2alpha(P) in mice with homozygous functional knockouts in the genes encoding the heme-regulated eIF2alpha kinase (HRI), or the amino acid-regulated eIF2alpha kinase (GCN2). A 10-fold increase in eIF2alpha(P) was observed in reperfused wild-type mice and in the HRI-/- or GCN2-/- mice. However, in all reperfused groups, the RNA-dependent protein kinase (PKR)-like endoplasmic reticulum eIF2alpha kinase (PERK) exhibited an isoform mobility shift on SDS-PAGE, consistent with the activation of the kinase. These data indicate that neither HRI nor GCN2 are required for the large increase in post-ischemic brain eIF2alpha(P), and in conjunction with our previous report that eIF2alpha(P) is produced in the brain of reperfused PKR-/- mice, provides evidence that PERK is the kinase responsible for eIF2alpha phosphorylation in the early post-ischemic brain.
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PMID:Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. 1138 92

Protein synthesis inhibition occurs in neurons immediately on reperfusion after ischemia and involves at least alterations in eukaryotic initiation factors 2 (eIF2) and 4 (eIF4). Phosphorylation of the alpha subunit of eIF2 [eIF2(alphaP)] by the endoplasmic reticulum transmembrane eIF2alpha kinase PERK occurs immediately on reperfusion and inhibits translation initiation. PERK activation, along with depletion of endoplasmic reticulum Ca2+ and inhibition of the endoplasmic reticulum Ca2+ -ATPase, SERCA2b, indicate that an endoplasmic reticulum unfolded protein response occurs as a consequence of brain ischemia and reperfusion. In mammals, the upstream unfolded protein response components PERK, IRE1, and ATF6 activate prosurvivial mechanisms (e.g., transcription of GRP78, PDI, SERCA2b ) and proapoptotic mechanisms (i.e., activation of Jun N-terminal kinases, caspase-12, and CHOP transcription). Sustained eIF2(alphaP) is proapoptotic by inducing the synthesis of ATF4, the CHOP transcription factor, through "bypass scanning" of 5' upstream open-reading frames in ATF4 messenger RNA; these upstream open-reading frames normally inhibit access to the ATF4 coding sequence. Brain ischemia and reperfusion also induce mu-calpain-mediated or caspase-3-mediated proteolysis of eIF4G, which shifts message selection to m 7 G-cap-independent translation initiation of messenger RNAs containing internal ribosome entry sites. This internal ribosome entry site-mediated translation initiation (i.e., for apoptosis-activating factor-1 and death-associated protein-5) can also promote apoptosis. Thus, alterations in eIF2 and eIF4 have major implications for which messenger RNAs are translated by residual protein synthesis in neurons during brain reperfusion, in turn constraining protein expression of changes in gene transcription induced by ischemia and reperfusion. Therefore, our current understanding shifts the focus from protein synthesis inhibition to the molecular pathways that underlie this inhibition, and the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain.
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PMID:Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. 1182 11

The rat homologue of a mitochondrial ATP-dependent protease Lon was cloned from cultured astrocytes exposed to hypoxia. Expression of Lon was enhanced in vitro by hypoxia or ER stress, and in vivo by brain ischemia. These observations suggested that changes in nuclear gene expression (Lon) triggered by ER stress had the potential to impact important mitochondrial processes such as assembly and/or degradation of cytochrome c oxidase (COX). In fact, steady-state levels of nuclear-encoded COX IV and V were reduced, and mitochondrial-encoded subunit II was rapidly degraded under ER stress. Treatment of cells with cycloheximide caused a similar imbalance in the accumulation of COX subunits, and enhanced mRNA for Lon and Yme1, the latter another mitochondrial ATP-dependent protease. Furthermore, induction of Lon or GRP75/mtHSP70 by ER stress was inhibited in PERK (-/-) cells. Transfection studies revealed that overexpression of wild-type or proteolytically inactive Lon promoted assembly of COX II into a COX I-containing complex, and partially prevented mitochondrial dysfunction caused by brefeldin A or hypoxia. These observations demonstrated that suppression of protein synthesis due to ER stress has a complex effect on the synthesis of mitochondrial-associated proteins, both COX subunits and ATP-dependent proteases and/or chaperones contributing to assembly of the COX complex.
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PMID:Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. 1208 77

Transient global cerebral ischemia triggers suppression of the initiation step of protein synthesis, a process which is controlled by endoplasmic reticulum (ER) function. ER function has been shown to be disturbed after transient cerebral ischemia, as indicated by an activation of the ER-resident eIF2alpha kinase PERK. In this study, we investigated ischemia-induced changes in protein levels and phosphorylation states of the initiation factors eIF2alpha, eIF2B epsilon, and eIF4G1 and of p70 S6 kinase, proteins playing a central role in the control of the initiation of translation. Transient focal cerebral ischemia was induced in mice by occlusion of the left middle cerebral artery. Transient ischemia caused a long-lasting suppression of global protein synthesis. eIF2alpha was transiently phosphorylated after ischemia, peaking at 1-3 h of recovery. eIF2B epsilon and p70 S6 kinase were completely dephosphorylated during ischemia and phosphorylation did not recover completely following reperfusion. In addition, eIF2B epsilon, eIF4G1, and p70 S6 kinase protein levels decreased progressively with increasing recirculation time. Thus, several different processes contributed to ischemia-induced suppression of the initiation of protein synthesis: a long-lasting dephosphorylation of eIF2B epsilon and p70 S6K starting during ischemia, a transient phosphorylation of eIF2alpha during early reperfusion, and a marked decrease of eIF2B epsilon, eIF4G1, and p70 S6K protein levels starting during vascular occlusion (eIF4G1). Study of the mechanisms underlying ischemia-induced suppression of the initiation step of translation will help to elucidate the role of protein synthesis inhibition in the development of neuronal cell injury triggered by transient cerebral ischemia.
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PMID:Mechanisms underlying suppression of protein synthesis induced by transient focal cerebral ischemia in mouse brain. 1242 99

A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane-bound proteins ATF6, IRE1alpha, and PERK. The authors simultaneously examined the activation of ATF6, IRE1alpha, and PERK, as well as components of downstream UPR pathways, in the rat brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2alpha phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in brain stem and hippocampus. PERK was degraded in vitro by mu-calpain. Although inactive IRE1alpha was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after brain ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.
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PMID:Dysfunction of the unfolded protein response during global brain ischemia and reperfusion. 1267 23

Upon brain reperfusion following ischemia, there is widespread inhibition of neuronal protein synthesis that is due to phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), which persists in selectively vulnerable neurons (SVNs) destined to die. Other investigators have shown that expression of mutant eIF2alpha (S51D) mimicking phosphorylated eIF2alpha induces apoptosis, and expression of non-phosphorylatable eIF2alpha (S51A) blocks induction of apoptosis. An early event in initiating apoptosis is the release of cytochrome c from mitochondria, and cytochrome c release corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. At present the signaling pathways leading to this are not well defined. We hypothesized that persistent eIF2alpha(P) reflects injury mechanisms that are causally upstream of release of cytochrome c and induction of apoptosis. At 4 h of reperfusion following 10-min cardiac arrest, vulnerable neurons in the striatum, hippocampal hilus and CA1 showed colocalized intense immunostaining for both persistent eIF2alpha(P) and cytoplasmic cytochrome c, while resistant neurons in the dentate gyrus and elsewhere did not immunostain for either. A lower intensity of persistent eIF2alpha(P) immunostaining was present in cortical layer V pyramidal neurons without cytoplasmic cytochrome c, possibly reflecting the lesser vulnerability of this area to ischemia. We did not observe cytoplasmic cytochrome c in any neurons that did not also display persistent eIF2alpha(P) immunostaining. Because phosphorylation of eIF2alpha during early brain reperfusion is carried out by PERK, these findings suggest that there is prolonged activation of the unfolded protein response in the reperfused brain.
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PMID:Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia. 1268 90

Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.
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PMID:Induction of neuronal death by ER stress in Alzheimer's disease. 1536 92

The endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptosis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.
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PMID:[The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes]. 1557 42

C5b-9-induced glomerular epithelial cell (GEC) injury in vivo (in passive Heymann nephritis) and in culture is associated with damage to the endoplasmic reticulum (ER) and increased expression of ER stress proteins. Induction of ER stress proteins is enhanced via cytosolic phospholipase A(2) (cPLA(2)) and limits complement-dependent cytotoxicity. The present study addresses another aspect of the ER unfolded protein response, i.e. activation of protein kinase R-like ER kinase (PERK or pancreatic ER kinase), which phosphorylates eukaryotic translation initiation factor 2-alpha (eIF2alpha), thereby generally suppressing translation and decreasing the protein load on a damaged ER. Phosphorylation of eIF2alpha was enhanced significantly in glomeruli of proteinuric rats with passive Heymann nephritis, compared with control. In cultured GECs, complement induced phosphorylation of eIF2alpha and reduced protein synthesis, and complement-stimulated phosphorylation of eIF2alpha was enhanced by overexpression of cPLA(2). Ischemia-reperfusion in vitro (deoxyglucose plus antimycin A followed by glucose re-exposure) also stimulated eIF2alpha phosphorylation and reduced protein synthesis. Complement and ischemia-reperfusion induced phosphorylation of PERK (which correlates with activation), and fibroblasts from PERK knock-out mice were more susceptible to complement- and ischemia-reperfusion-mediated cytotoxicity, as compared with wild type fibroblasts. The GEC protein, nephrin, plays a key role in maintaining glomerular permselectivity. In contrast to a general reduction in protein synthesis, translation regulated by the 5'-end of mouse nephrin mRNA during ER stress was paradoxically maintained, probably due to the presence of short open reading frames in this mRNA segment. Thus, phosphorylation of eIF2alpha and consequent general reduction in protein synthesis may be a novel mechanism for limiting complement- or ischemia-reperfusion-dependent GEC injury.
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PMID:Role of the endoplasmic reticulum unfolded protein response in glomerular epithelial cell injury. 1586 8

After ischemia, endoplasmic reticulum (ER) stress pathways are activated that include unfolded protein response (UPR) and protein synthesis inhibition (PSI). Both of these mechanisms aim to restore ER functioning mainly by inhibition of translation and increased processing of excess proteins in ER. We were interested in the role of these pathways during spontaneous recovery after transient middle cerebral artery occlusion (MCAO) in rats. The spontaneous recovery of rats was assessed with a limb-placing test. The expression of ER-stress-related genes (IRE1, ATF6, GRP78, eif2alpha, ATF4, PERK) was studied by using in situ hybridization in different brain areas on post-operative days 2, 7, 14 and 28. Elevated signals were detected in striatum contralateral to the lesion on days 2 (PERK and IRE1) and 14 post-ischemia (IRE1). Gene expression was elevated on day 7 in the striatum ipsilateral to the lesion (ATF6 and GRP78) and on day 14 (GRP78) post-ischemia. Furthermore, elevated levels of GRP78 were detected on day 14 after ischemia in the ipsilateral sensorimotor cortex. These results suggest that altered gene expression related to unfolded protein response may be more long lasting than expected following focal cerebral ischemia. In addition, these results show that the response to ER stress differs ipsi- and contralaterally after MCAO in rats. Since these differences are detected in both hemispheres only in areas adjacent to the lesion, UPR may contribute to spontaneous recovery after MCAO in rats.
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PMID:Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke. 1668 12

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