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)

Canine myocardium was exposed to bouts of low-flow ischemia to identify the interactions that develop between the microtubule-based cytoskeleton and the heat shock protein 70 (HSP70) family of heat shock proteins in viable cardiomyocytes. "Moderate" or "severe" low-flow ischemia was produced in chronically instrumented dogs by reducing circumflex coronary flow by 50% for 2 h or by 75% for 5 h followed by reperfusion for 2 and 24 h, respectively. Electron and immunofluorescence microscopy demonstrated either partial or nearly complete depolymerization of the intermyofibrillar microtubules in areas of myofibril disruption and partial dissolution of the perinuclear microtubule girdle. In contrast, centrosomal tubulin arrays appeared to remain intact following low-flow ischemia. In cardiomyocytes displaying myofibril disruption, constitutively expressed HSP73 (HSC73) colocalized with intact but not disrupted microtubules and with perinuclear and centrosomal tubulin following moderate ischemia. Microtubule depolymerization and high molecular weight tubulin-HSC73 complexes were present in more severely ischemic tissue. These results suggest that HSC73 directly interacts with tubulin and may protect selected elements of the microtubule network and limit myofibril disruption during reversible low-flow ischemia.
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PMID:HSC73-tubulin complex formation during low-flow ischemia in the canine myocardium. 1223 82

Glutamate-induced excitotoxicity is associated with a selective loss of retinal neurons after retinal ischemia and possibly in glaucoma. Since heat shock protein (HSP) 70 is known to play a protective role against ischemic neuronal injury, which is also linked to excitotoxicity, we studied the expression of inducible (HSP72) and constitutive (HSC70) forms of HSP70 in apoptosis of retinal ganglion cells (RGCs) after intravitreal injection of 8 nmoles N-methyl-D-aspartate (NMDA), a glutamate receptor agonist. Approximately 18 h after NMDA injection, there were increased numbers of TUNEL-positive cells and cells with elevated HSP72 immunoreactivity in the retinal ganglion cell layer (RGCL), but there were no noticeable changes in HSC70 immunoreactivity. These HSPs positive cells were also Thy-1 positive, a marker for RGCs. Hyperthermic pre-conditioning, which is known to induce HSPs, given 6 or 12 h prior to NMDA injection ameliorated neuronal loss in the RGCL as counted 7 days after NMDA injection but pre-conditioning at 18 h prior to NMDA injection did not have any ameliorative effect. Quercetin, an inhibitor of HSP synthesis, abolished the ameliorative effect of hyperthermic pre-conditioning. Pre-conditioning elevated HSP72 but not HSC70 immunoreactivity and reduced the number of TUNEL-positive cells in the RGCL at 18 h. Our results suggest that intravitreal injection of NMDA induces an up-regulation of HSP72 in a time-dependent manner but not HSC70 in RGCs, indicating a stress response of HSP72 in RGCs and other inner retinal neurons after exposure to NMDA. Hyperthermic pre-conditioning given within a therapeutic window is neuroprotective to the retina against NMDA-induced excitotoxicity, likely by inhibiting apoptosis through the modulation of HSP72 expression.
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PMID:Hyperthermic pre-conditioning protects retinal neurons from N-methyl-D-aspartate (NMDA)-induced apoptosis in rat. 1270 53

BAG-1 (Bcl-2-associated athanogene-1) proteins interact with the HSC70 and HSP70 heat shock proteins and have been proposed to promote cell survival by coordinating the function of these chaperones with the proteasome to facilitate protein degradation. Consistent with this proposal, previous analyses in cancer cells have demonstrated that BAG-1 requires protein domains important for HSC70/HSP70 and proteasome binding in order to interfere with the growth inhibition induced by heat shock (Townsend, P. A., Cutress, R. I., Sharp, A., Brimmell, M., and Packham, G. (2003) Cancer Res., 63, 4150-4157). Moreover, cellular stress triggered the relocalization of the cytoplasmic BAG-1S (approximately 36 kDa) isoform to the nucleus, and both BAG-1S and the constitutively nuclear localized BAG-1L (approximately 50 kDa) isoform suppressed heat shock-induced apoptosis to the same extent, suggesting a critical role in the nucleus. Because ischemia (I) and reperfusion (R) are important stress signals in acute and chronic heart disease, we have examined the expression and function of BAG-1 proteins in primary cardiac myocytes (CMs) and the Langendorff-perfused intact heart. The expression of both BAG-1 isoforms, BAG-1S and BAG-1L, was rapidly induced following ischemia in rat CM, and this was maintained during subsequent reperfusion. In control hearts, BAG-1S and BAG-1L were readily detectable in both the nucleus and the cytoplasm. However, BAG-1S did not relocate to the nucleus following simulated I/R. BAG-1 interacted with both RAF-1 and HSC70 in CMs and the whole heart, and binding to HSC70 was increased following I/R. Overexpression of the human BAG-1S and BAG-1 M isoforms significantly reduced CM apoptosis following simulated I/R. By contrast, BAG-1L or BAG-1S fused to a heterologous nuclear localization sequence failed to protect CM. Finally, overexpression of BAG-1 deletion and point mutants unable to bind HSC70/HSP70 failed to offer cardioprotection. Surprisingly, a deletion mutant lacking the N-terminal ubiquitin-like domain, which mediates interaction with the proteasome, still promoted cardioprotection. Therefore, BAG-1 has a novel cardioprotective role, mediated via association with HSC70/HSP70, which is critical upon cytoplasmic localization but independent of the BAG-1 ubiquitin-like domain. Our studies demonstrate that BAG-1 can influence cellular response to stress by multiple mechanisms, potentially influenced by the cell type and nature of the stress signal.
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PMID:BAG-1 proteins protect cardiac myocytes from simulated ischemia/reperfusion-induced apoptosis via an alternate mechanism of cell survival independent of the proteasome. 1497 28

Brain ischemia and reperfusion (I/R) induce neuronal intracellular stress responses, including the heat-shock response (HSR) and the unfolded protein response (UPR), but the roles of each in neuronal survival or death are not well understood. We assessed the relative expression of UPR (ATF4, CHOP, GRP78, XBP-1) and HSR-related (HSP70 and HSC70) mRNAs and proteins after brain I/R. We evaluated these in hippocampal CA1 and CA3 after normothermic, transient global forebrain ischemia and up to 42 h of reperfusion. In CA1, chop and xbp-1 mRNA showed maximal 14- and 12-fold increases, and the only protein increase observed was for 30-kDa XBP-1. CA3 showed induction of only xbp-1. GRP78 protein declined in CA1, but increased twofold and then declined in CA3. Transcription of hsp70 was an order of magnitude greater than that of any UPR-induced transcript in either CA1 or CA3. HSP70 translation in CA1 lagged CA3 by approximately 24 h. We conclude that (a) in terms of functional end products, the ER stress response after brain ischemia and reperfusion more closely resembles the integrated stress response than the UPR; and (b) the HSR leads to quantitatively greater mRNA production in postischemic neurons, suggesting that cytoplasmic stress predominates over ER stress in reperfused neurons.
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PMID:Hippocampal cellular stress responses after global brain ischemia and reperfusion. 1771 97

Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), which is one of the substrates of protein phosphatase 1 (PP1), occurs rapidly during the first minutes of post-ischemic reperfusion after an episode of cerebral ischemia. In the present work, two experimental models of transient global ischemia and ischemic tolerance (IT) were used to study PP1 interacting/regulatory proteins following ischemic reperfusion. For that purpose we utilized PP1 purified by microcystin chromatography, as well as 2D DIGE of PP1alpha and PP1gamma immunoprecipitates. The highest levels of phosphorylated eIF2alpha found after 30 min reperfusion in rats without IT, correlated with increased levels in PP1 immunoprecipitates of the inhibitor DARPP32 as well as GRP78 and HSC70 proteins. After 4 h reperfusion, the levels of these proteins in PP1c complexes had returned to control values, in parallel to a significant decrease in eIF2alpha phosphorylated levels. IT that promoted a decrease in eIF2alpha phosphorylated levels after 30 min reperfusion induced the association of GADD34 with PP1c, while prevented that of DARPP32, GRP78, and HSC70. Different levels of HSC70 and DARPP32 associated with PP1alpha and PP1gamma isoforms, whereas GRP78 was only detected in PP1gamma immunoprecipitates. Here we suggest that PP1, through different signaling complexes with their interacting proteins, may modulate the eIF2alpha phosphorylation/dephosphorylation during reperfusion after a transient global ischemia in the rat brain. Of particular interest is the potential role of GADD34/PP1c complexes after tolerance acquisition.
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PMID:Regulatory proteins of eukaryotic initiation factor 2-alpha subunit (eIF2 alpha) phosphatase, under ischemic reperfusion and tolerance. 1776 Aug 64


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