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)

Geranylgeranylacetone (GGA), an anti-ulcer agent, has anti-inflammatory potential against experimental colitis and ischemia-induced renal inflammation. However, molecular mechanisms involved in its anti-inflammatory effects are largely unknown. We found that, in glomerular mesangial cells, GGA blocked activation of nuclear factor-kappaB and consequent induction of monocyte chemoattractant protein 1 (MCP-1) by inflammatory cytokines. It was inversely correlated with induction of unfolded protein response (UPR) evidenced by expression of 78kDa glucose-regulated protein (GRP78) and suppression of endoplasmic reticulum stress-responsive alkaline phosphatase. Various inducers of UPR including tunicamycin, thapsigargin, A23187, 2-deoxyglucose, dithiothreitol, and AB(5) subtilase cytotoxin reproduced the suppressive effects of GGA. Furthermore, attenuation of UPR by stable transfection with GRP78 diminished the anti-inflammatory effects of GGA. These results disclosed a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of GGA.
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PMID:Blunted activation of NF-kappaB and NF-kappaB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response. 1797 Dec 94

Endoplasmic reticulum (ER) stress, which is caused by an accumulation of unfolded proteins in the ER lumen, is associated with stroke and with neurodegenerative diseases such as Parkinson's and Alzheimer diseases. We assessed the expression patterns of immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein (GRP) 78 (an ER-resident molecular chaperone whose expression serves as a good marker of ER-stress), activating transcription factor (ATF)-4, and C/EBP homology protein (CHOP) by immunohistochemistry and/or Western blotting after transient forebrain ischemia in gerbils. Double-fluorescent staining involving CHOP immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) method was performed to clarify the involvement of CHOP in cell death. Immunohistochemical and Western blot analyses of the hippocampal Cornet d'Ammon (CA)1 subfield showed that BiP expression was increased at 12 h, peaked at 3 days, then decreased (versus the control group). A transient increase was detected in CA3 at 1 day after ischemia, but BiP expression was unchanged in dentate gyrus and cortex. Signals for ATF-4 and CHOP were increased at 1 day and 3 days in CA1, and at 12 h in CA3. Co-localization of CHOP immunoreactivity and DNA fragmentation was detected by the TUNEL method at 3 days after ischemia in CA1, but not at 12 h in CA3. These findings are consistent with ER stress playing a pivotal role in post-ischemic neuronal death in the gerbil hippocampal CA1 subfield.
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PMID:Involvement of endoplasmic reticulum stress in the neuronal death induced by transient forebrain ischemia in gerbil. 1808 69

Although renal ischemia-reperfusion is known to activate the unfolded protein response, the renal site and role of activation of this response following the insult in vivo remains largely unknown. Here we studied the renal spatio-temporal expression pattern of glucose-regulated protein (GRP) 78, a central regulator of the unfolded protein response network, following renal ischemia-reperfusion and the effects of the specific chemical unfolded protein response inducers, tunicamycin and thapsigargin, on renal ischemia-reperfusion injury in mice. Renal ischemia-reperfusion resulted in expression of the spliced form of the X-box binding protein-1 (XBP-1s) transcript, an unfolded protein response target, at 1 and 2 h after the insult. This response was followed by an increase in the GRP78 transcript and protein. The increased amount of GRP78 protein after ischemia-reperfusion was largely localized in proximal tubule cells. Pretreatment with tunicamycin or thapsigargin significantly ameliorated renal dysfunction and injury after ischemia-reperfusion. Taken together with these results, the unfolded protein response was activated following renal ischemia-reperfusion at sites that are susceptible to ischemia-reperfusion injury, and this activation had a protective effect against renal ischemia-reperfusion injury in vivo. Molecules involved in the unfolded protein response may offer new opportunities for pharmacological intervention against renal ischemia-reperfusion injury, which is an important cause of acute kidney injury.
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PMID:A protective role of unfolded protein response in mouse ischemic acute kidney injury. 1864 64

Recent studies have suggested that neuronal apoptosis in cerebral ischemia could arise from dysfunction of endoplasmic reticulum (ER) and mitochondria. B-cell lymphoma/leukemia-2 gene (Bcl-2) has been described as an inhibitor both in programmed cell death (PCD) and ER dysfunction during apoptosis, and the Bcl-2 family play a key role in regulating the PCD, both locally at the ER and from a distance at the mitochondrial membrane. However, its signal pathways and concrete mechanisms in endoplasmic reticulum-initiated apoptosis remain incompletely understood. We therefore investigate whether ischemia/reperfusion (I/R) causes neuronal apoptosis in part via cross-talk between ER and mitochondria or not, and how the overexpression of Bcl-2 prevents this form of cell death. Here we show that analogous I/R-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. The participation of the mitochondrial pathway was demonstrated by the release of cytochrome C (cyt C) from mitochondrial into cytoplasmic fractions and caspase-9 cleavage. The involvement of ER stress was further supported by the observable increase of glucose-regulated protein 78(GRP78)/BiP expression and caspase-12 activity. Furthermore, prior to these changes, swelling of the ER lumen and dissociation of ribosomes from rough ER were detected by electron microscopy. Bcl-2 overexpression inhibits the release of cyt C and the activation of caspase-9/-8/-3 but not caspase-12 based on the results of Western blot. These suggest that cross-talk between ER and mitochondria participate in neuronal damage after ischemia/reperfusion. Bcl-2 overexpression could suppress I/R-induced neuronal apoptosis via influencing mitochondrial integrity.
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PMID:The protection of Bcl-2 overexpression on rat cortical neuronal injury caused by analogous ischemia/reperfusion in vitro. 1872 55

Mild NMDA receptor activation is correlated with neuroprotection in models of cerebral ischemia. Neuroprotection with NMDA manifests as a form of ischemic tolerance and involves the induction of cellular stress systems sensitive to disturbances in cellular calcium homeostasis. Unilateral micro-injection of 10, 160 and 320 microM NMDA into the prefrontal cortex of a rat 30 min prior to permanent occlusion of the middle cerebral artery (MCAO) significantly reduced the area of infarct observed after 4 h of ischemia. The highest dose of NMDA (320 microM) prevented the propagation of ischemic damage through a direct toxicity on neuronal tissue adjacent to the injection site as demonstrated in thionin-stained sections. As a result, the degree of ischemia-induced damage was similar to that measured in rats pretreated with the low dose of NMDA (10 microM). Expression of heat shock protein (HSP) 70 and glucose-regulated protein (GRP) 94 in cortical samples taken from the region of infarct following MCAO was significantly reduced in rats pretreated with 10 microM NMDA compared to saline-injected control rats and rats pretreated with higher doses of NMDA. Furthermore, 10 microM NMDA did not appear to influence expression of m-calpain or GRP78, however, higher doses of NMDA did significantly induce expression of both proteins as assessed by Western blotting. In summary, our data demonstrate an in vivo rodent model of ischemic tolerance in which 30 min of neuronal preconditioning with 10 microM NMDA confers protection against a 4 h period of MCAO-induced ischemia. This effect may involve modulation of cellular stress signals, in particular HSP70 and GRP94.
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PMID:Ischemic tolerance following low dose NMDA involves modulation of cellular stress proteins. 1899 20

Apolipoprotein E-deficient (apoE(-/-)) mice have been shown to have increased vulnerability to neuronal damage induced by cerebral ischemia; however, the mechanism of this increased vulnerability remains unclear. In order to define the role of the apoE protein against ischemia-induced ER stress and cell death, experiments were performed to compare ER stress-associated chaperones and signal proteins in the hippocampus of apoE(-/-) mice to those of WT mice after being subjected to forebrain ischemia and reperfusion. Although neuronal loss in area CA1-CA3 of the hippocampus was observed 3 days after ischemia in both types of mice, the damage in apoE(-/-) mice was more severe. In apoE(-/-) mice, a more extensive increase in 78-kDa glucose-regulated protein (GRP78) was observed after the insult, whereas the level of GRP94 was not changed. The expression of both C/EBP homologous protein (CHOP) and caspase-12 was increased in the hippocampus in both WT and apoE(-/-) mice after ischemia. The increased levels of CHOP in apoE(-/-) mice were significantly higher than those in WT mice, whereas the levels of caspase-12 in the two were comparable. Furthermore, whereas the levels of c-Jun N-terminal kinase (JNK), p-JNK1 and p-JNK2 in WT mice were unchanged after ischemia, they were significantly increased in apoE(-/-) mice 24h and 48h after ischemia. These results suggest that increased vulnerability of the hippocampus to forebrain ischemia and reperfusion in apoE(-/-) mice is at least partly attributable to perturbed induction of an ER chaperone, GRP 94, and enhancement of the CHOP- and JNK-dependent apoptotic pathway in the hippocampus.
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PMID:Apolipoprotein E-deficient mice are more vulnerable to ER stress after transient forebrain ischemia. 1942 81

Ischemia/reperfusion (I/R) unleashes cellular events that threaten organ survival. I/R affects endoplasmic reticulum (ER) integrity and initiates the unfolded protein response (UPR). The adaptive arm of the UPR attenuates ER stress by increasing expression of chaperones promoting proper protein folding. However, failure to resolve ER stress leads to apoptotis. We recently showed that prolyl hydroxylase inhibition (PHI) attenuated post-ischemic cardiac injury. We hypothesized that PHI attenuated myocardial I/R injury through modulation of the UPR. We show for the first time that PHI activates all three regulatory arms of the UPR in murine microvascular endothelial cells and in mouse hearts. Cardiac I/R activated expression of pro-apoptotic CHOP (2.8 fold, n=3, p<0.01). PHI significantly decreased CHOP expression (50%, n=3, p<0.05) in post-ischemic hearts. PHI also induced activating transcription factor 4 (3.5 fold, n=3, p<0.001), glucose-regulated protein 78 (6 fold, n=3, p<0.001) and ER degradation-enhancing alpha-mannosidase-like protein (2.8 fold, n=3, p<0.001) expression in reperfusing hearts. Thus PHI resulted in significant reduction of apoptosis in post-ischemic myocardium. Our studies suggest that PHI induces protective ER stress proteins and attenuates post-ischemic myocardial damage by decreasing the pro-apoptotic components of the UPR.
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PMID:Prolyl hydroxylase inhibition attenuates post-ischemic cardiac injury via induction of endoplasmic reticulum stress genes. 1952 66

In animal models, endoplasmic reticulum (ER) stress and apoptosis take place around cerebral infarction areas during ischemia, which presumably protect tissues from necroses-induced injury as well as promote cells toward death. We examined whether these pathological changes, especially temporal occurrence, were present in patients who suffered from cerebral ischemia. The studies by immunohistochemistry show that ER chaperone glucose-regulated protein (GRP78) and caspase-9 elevate around infarction areas. The experiments by terminal deoxynucleotidy transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick-end labeling (TUNEL) illustrate that TUNEL-positive cells are higher around infarction tissues than controls. Moreover, GRP78, caspase-9 and TUNEL cells emerge one after another during ischemia. In conclusion, ER stress, apoptosis initiation and DNA fragment develop sequentially in ischemic human brain. ER stress during excessive ischemia stimulates apoptotic cell death beyond activating a defense for nerve cells being away from injury.
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PMID:Ischemia induces endoplasmic reticulum stress and cell apoptosis in human brain. 2034 37

Transient forebrain ischemia has been shown to cause neuronal injury in the CA1 area of the hippocampus in mice. In addition to neuronal injury, astrocytes in area CA1 undergo apoptosis under ischemic conditions. Although failure of impaired astrocytes to take up glutamate is thought to contribute to the pathogenesis of cerebral ischemia, the molecular mechanism underlying this phenomenon remains unexplored. In the present study, we investigated neuronal and astroglial responses to endoplasmic reticulum (ER) stress, which is an important sequela of transient forebrain ischemia in the hippocampus of mice. Cellular injury was observed in area CA1 of the hippocampus 72h after reperfusion, and ssDNA positivity was detectable in some glial cells as well as neurons in this area. An increase of 78-kDa glucose-regulated protein (GRP78), an indicator of ER stress, was detected in pyramidal neurons and astrocytes in this area after the insult. Immunohistochemical analysis showed that caspase-12 was increased in pyramidal neurons and astrocytes located in the extrapyramidal cell layer. Immunoreactivity for C/EBP homologous protein (CHOP) was increased significantly in pyramidal cells but not in astrocytes. These results suggest that astrocytes as well as pyramidal neurons in area CA1 undergo apoptosis through an ER stress-dependent mechanism after ischemia. Unlike the situation in neuronal apoptosis, CHOP does not play a role in the cell death of astrocytes.
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PMID:Characterization of neuronal and astroglial responses to ER stress in the hippocampal CA1 area in mice following transient forebrain ischemia. 2036 24

Myocardial ischemia is a severe stress condition that causes extensive biochemical changes triggering cardiac cell death. The 78-kDa glucose-regulated protein (GRP78), a heat shock protein present in all cells and a widely used marker of endoplasmic reticulum stress, functions in controlling the structural maturation of nascent glycoproteins. However, GRP78 was also found to be expressed on the cell surface of several cells such as endothelial cells, macrophages, and tumor cells where it functions as a receptor for a variety of ligands in signaling pathways. Recently, we have identified peptides from two different sources that specifically bind GRP78 protein. We have shown that binding of these peptides to endothelial cell surface GRP78 resulted in angiogenesis. In this study, we first established the presence of cell surface GRP78 on cardiac myocytes. Analysis of cardiomyocytes under hypoxia determined the significant increase in cell surface GRP78 in addition to gene expression and total protein. Apoptosis that was significantly increased in cardiomyocytes under hypoxic conditions was inhibited by the presence of the peptide-binding GRP78 during hypoxia. Inhibition of apoptosis was mediated by the binding of the peptide to cardiomyocytes cell surface GRP78 resulting in blocking caspase-3/7 activation. Silencing GRP78 RNA that reduced GRP78 receptor abrogated the peptide activity. Apoptosis of cardiac cells induced by myocardial infarction in a mouse model was also significantly inhibited by the administration of the peptide to mouse hearts. Our findings may make ADoPep1 a useful therapeutic tool for relieving of ischemia.
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PMID:Peptide-binding heat shock protein GRP78 protects cardiomyocytes from hypoxia-induced apoptosis. 2066 93


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