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)

Rats were subjected to transient cerebral ischemia by four-vessel occlusion of 30 min duration, followed by 2, 4, 8 or 24 h of recovery. Total RNA was isolated from the cerebral cortex and hippocampus, and reverse transcribed into cDNA. Hsp40 mRNA levels of samples were evaluated by quantitative PCR. Transient cerebral ischemia caused a marked increase in hsp40 mRNA levels to about 250% and 500% of control in the cortex and hippocampus respectively. Since hsp40 exerts a critical regulatory function in the HSC70/HSP70 ATPase cycle, an ischemia-induced rise of hsp40 mRNA levels could mark the onset of the recovery process after transient ischemia. On the other hand, the inhibitory action of hsp40 on P58 (a protein that activates protein synthesis by blocking the interferon-induced double-stranded RNA-activated protein kinase PKR) implies that the rise in hsp40 expression may equally well contribute to the post-ischemic suppression of protein synthesis.
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PMID:Effects of transient cerebral ischemia on hsp40 mRNA levels in rat brain. 958 51

When ischemic brain is reperfused, there is in vulnerable neurons immediate inhibition of protein synthesis associated with a large increase in phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 [eIF2alpha, phosphorylated form eIF2alpha(P)]. We examined eIF2alpha kinase and eIF2alpha(P) phosphatase activity in brain homogenate postmitochondrial supernatants obtained from rats after 3 to 30 min of global brain ischemia (cardiac arrest), after 5 min of ischemia and 5 min of reperfusion (5R), and after 10 min of ischemia and 90 min reperfusion (90R). Because it has been suggested that PKR might be specifically responsible for producing eIF2alpha(P) during reperfusion, we also examined in brain homogenates from wild-type and PKR0/0 C57BL/6J x 129/SV mice the effect of 5 min of ischemia and 5 min of reperfusion on eIF2alpha(P). Cytosolic brain eIF2alpha(P) in the 5R and 90R rats was 18- and 23-fold that of nonischemic controls without any change in the rate of eIF2alpha(P) dephosphorylation. There was no change in eIF2alpha kinase activity between 3 and 30 min of ischemia but an 85% decrease in the 5R group; the 90R group was similar to controls. In wild-type and PKR0/0 mice total eIF2alpha was identical, and there was an identical 16-fold increase in eIF2alpha(P) at 5 min of reperfusion. Our observations contradict hypotheses that PKR activation, loss of eIF2alpha(P) phosphatase activity, or any general increase in eIF2alpha kinase activity are responsible for reperfusion-induced phosphorylation of eIF2alpha, and we suggest that the mechanism may involve regulation of the availability of eIF2alpha to a kinase.
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PMID:Eukaryotic initiation factor 2alpha kinase and phosphatase activity during postischemic brain reperfusion. 1007 97

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

Shutdown of translation is a highly conserved response of cells to a severe form of metabolic, thermal, or physical stress. After the metabolic stress induced by transient cerebral ischemia, translational recovery is observed only in cells that withstand the transient interruption of blood supply, implying that restoration of translation critically determines the final outcome. On the other hand, apoptosis is believed to play a role in ischemia-induced cell death. Apoptosis is an active process that is blocked by agents known to suppress protein synthesis. Thus, the question arises whether stress-induced suppression of protein synthesis is protective or toxic for the affected cells. Accepting the notion that endoplasmic reticulum (ER) dysfunction is the mechanism underlying shutdown of translation after transient cerebral ischemia, an attempt may be made to try to solve the protein synthesis paradox by understanding the role of protein synthesis suppression in conditions associated with ER dysfunction. Endoplasmic reticulum dysfunction-induced accumulation of unfolded proteins in the ER lumen is the trigger of two signal transduction pathways: PKR-like ER kinase-induced shutdown of translation to suppress new synthesis of proteins that cannot be correctly folded, and IRE1-induced expression of ER stress genes, a protein synthesis-dependent pathway needed to restore ER functions. Together these comprise the unfolded protein response. They are also induced after transient ischemia, implying a dual effect of protein synthesis suppression, a protective and a pathologic effect during early and prolonged reperfusion.
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PMID:Shutdown of translation: lethal or protective? Unfolded protein response versus apoptosis. 1284 81

Lack of recovery from protein synthesis inhibition (PSI) closely correlates with neuronal death following brain ischemia and reperfusion. It has therefore been suggested that understanding the mechanisms of PSI will shed light on the mechanisms of selective neuronal death following ischemia and reperfusion. It is now known that the PKR-like ER kinase (PERK)-mediated phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) causes translation inhibition at initial reperfusion. Activation of PERK, in turn, indicates endoplasmic reticulum stress and activation of the unfolded protein response. However, phosphorylation of eIF2alpha is a transient event and can account for PSI only in the initial hours of reperfusion. Although a number of other regulators of protein synthesis, such as eIF4F, 4EBP-1, eEF-2, and S6 kinase, have been assessed following cerebral ischemia and reperfusion, the causes of prolonged PSI have yet to be fully elucidated. The purpose of the present article is to bring together the evidence indicating that, at minimum, postischemic PSI should be conceptualized as consisting of two components: an acute, transient component mediated by unfolded protein response-induced eIF2alpha phosphorylation and a longer term component that correlates with neuronal death. Ischemic tolerance appears to separate the acute and persistent components of reperfusion-induced translation inhibition. Specific models of the relationship among acute PSI, persistent PSI, and neuronal death are presented to clarify issues that have emerged from ongoing work in this area.
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PMID:Acute and persistent protein synthesis inhibition following cerebral reperfusion. 1533 96

Inhibition of protein synthesis occurs in the post-ischemic reperfused kidney but the molecular mechanism of renal translation arrest is unknown. Several pathways have been identified whereby cell stress inhibits translation initiation via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF 2 alpha, phospho-form eIF 2 alpha(P)]. Here, we report a 20-fold increase in eIF 2 alpha(P) in kidney homogenates following 10 min of cardiac arrest-induced ischemia and 10 min reperfusion. Using immunohistochemistry, we observed eIF 2 alpha(P) in tubular epithelial cells in both cortex and medulla, where the greatest eIF 2 alpha(P) staining was found in epithelial cells of the so-called watershed area at the corticomedullary junction. We further show that increased eIF 2 alpha(P) is accompanied by activation of the PKR-like endoplasmic reticulum eIF 2 alpha kinase (PERK). These observations indicate that renal ischemia and reperfusion induce stress to the endoplasmic reticulum and activate the unfolded protein response in renal epithelial cells. As the unfolded protein response can result alternatively in a pro-survival or pro-apoptotic outcome, the present study demonstrates an new additional mechanism involved in cell damage and/or repair in ischemic and reperfused kidney.
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PMID:Renal ischemia and reperfusion activates the eIF 2 alpha kinase PERK. 1593 77

Visceral organs display differential sensitivity to ischemia and reperfusion injury, but the cellular mechanisms underlying these differential responses are not completely understood. A significant response to ischemia identified in brain is stress to the endoplasmic reticulum (ER), as indicated by PKR-like endoplasmic reticulum eIF2alpha kinase (PERK)-mediated phosphorylation of eIF2alpha. To determine the generality of this response, we evaluated the PERK pathway in brain, GI tract, heart, liver, lung, kidney, pancreas and skeletal muscle following a clinically relevant, 10 min cardiac arrest-induced whole body ischemia and either 10 or 90 min reperfusion. The potential role of nitric oxide (NO) on PERK activation was investigated by conducting ischemia and reperfusion in the presence and absence of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). Organ stress could be ranked with respect to the degree of eIF2alpha phosphorylation at 10 min reperfusion. Brain, kidney and GI tract were reactive organs, showing 15 to 20-fold increases in eIF2alpha(P) compared to controls. Moderately reactive organs included liver and heart, showing <10-fold increases in eIF2alpha(P). Pancreas, lung and skeletal muscle were nonreactive. Although treatment of cultured neuroblastoma 104 cells with the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP) activated PERK, administration of L-NAME had no effect on PERK activation or eIF2alpha phosphorylation in organs following ischemia and reperfusion. Thus, PERK is activated differentially in reperfused organs independent of NO. These results suggest that ER stress may play a role in differential responses of viscera to ischemia and reperfusion. ER stress in viscera may contribute to the pathophysiology of resuscitation from cardiac arrest and during organ transplantation procedures.
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PMID:PERK is activated differentially in peripheral organs following cardiac arrest and resuscitation. 1602 20

The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1alpha. Since TNF and FasL-induced hepatocyte apoptosis is implicated in a wide range of liver diseases, including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-XL or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c-based method useful for the diagnosis and monitoring of fulminant hepatitis.
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PMID:Apoptosis in liver diseases--detection and therapeutic applications. 1625 9

Endoplasmic reticulum (ER) stress transducers IRE1 (inositol requiring 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. Recently, we identified OASIS (old astrocyte specifically induced substance) as a novel ER stress transducer expressed in astrocytes. We report here that BBF2H7 (BBF2 human homolog on chromosome 7), an ER-resident transmembrane protein with the bZIP domain in the cytoplasmic portion and structurally homologous to OASIS, is cleaved at the membrane in response to ER stress. The cleaved fragments of BBF2H7 translocate into the nucleus and can bind directly to cyclic AMP-responsive element sites to activate transcription of target genes. Interestingly, although BBF2H7 protein is not expressed under normal conditions, it is markedly induced at the translational level during ER stress, suggesting that BBF2H7 might contribute to only the late phase of unfolded protein response signaling. In a mouse model of focal brain ischemia, BBF2H7 protein is prominently induced in neurons in the peri-infarction region. Furthermore, in a neuroblastoma cell line, BBF2H7 overexpression suppresses ER stress-induced cell death, while small interfering RNA knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, our results suggest that BBF2H7 is a novel ER stress transducer and could play important roles in preventing accumulation of unfolded proteins in damaged neurons.
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PMID:BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer. 1717 27

The goals of this work were first to assess whether the lactic acidosis observed in vivo in ischemia may by itself explain the inhibition of protein synthesis described in the literature and second to study the factors controlling the initiation of protein synthesis under lactic acid stress. Primary rat astrocyte cultures exposed to pH 5.25 underwent cell death and a strong inhibition of protein synthesis assessed by [3H]methionine incorporation, which was solely due to acidity of the extracellular medium and was not related to lactate concentrations. This result was associated with a weak phosphorylation of eukaryotic initiation factor (eIF)4E and a rapid phosphorylation of eIF2alpha via the kinases PKR and PKR-like endoplasmic reticulum kinase. The inhibition of PKR by PRI led first to a significant but not complete dephosphorylation of eIF2alpha that probably contributed to maintain the inhibition of the protein synthesis and second to surprising phosphorylations of extracellular signal-regulated protein kinase, p70S6K and eIF4E, suggesting a possible cross-link between the two pathways. Conversely, cell death was weak at pH 5.5. Protein synthesis was decreased to a lesser extent, the phosphorylation of eIF2alpha was limited, extracellular signal-regulated protein kinase 1/2 was activated and its downstream targets, p70S6K and eIF4E, were phosphorylated. However, the strong phosphorylation of eIF4E was not associated with an activation of the eIF4F complex. This last result may explain why protein synthesis was not stimulated at pH 5.5. However, when astrocytes were exposed at pH 6.2, corresponding to the lower pH observed in hyperglycemic ischemia, no modification in protein synthesis was observed. Consequently, lactic acidosis cannot, by itself, provide an explanation for the decrease in protein synthesis previously reported in vivo in ischemia.
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PMID:Regulation of initiation factors controlling protein synthesis on cultured astrocytes in lactic acid-induced stress. 1768 44


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