Acute and persistent protein synthesis inhibition following cerebral reperfusion

DeGracia, Donald J.

doi:10.1002/jnr.20225

Cited by 38 publications

(40 citation statements)

References 32 publications

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“…Alleviation of ER stress through the UPR can cause further accumulation of ROS from the UPR-regulated oxidative machinery in the ER and from the mitochondria (40). Weakening of the antioxidant defense systems by suppression of translation of the principal antioxidant enzymes, such as manganese and copper/zinc superoxide dismutase (SOD), catalase, and glutathione peroxidase, as a result of protein synthesis inhibition (PSI) after ischemic insult or sustained ER stress, may also sensitize cells to oxidative injury/death (13,34,41). However, our immunoblotting results did not reveal any change in the protein concentrations of these enzymes under sustained activation of ER stress (data not shown).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Endoplasmic reticulum stress exacerbates ischemia‐reperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells

Yung¹,

Korolchuk²,

Tolkovsky³

et al. 2006

FASEB j.

115

118

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Oxidative stress is central to ischemia-reperfusion injury. The role of the endoplasmic reticulum (ER) in this process is uncertain. In ER signaling, PERK-Nrf2 and Ire-CHOP are two pathways that determine cell fate under stress. PERK-Nrf2 up-regulates antioxidant enzyme expression whereas Ire-CHOP promotes apoptosis. We have identified a novel pathway in ER stress-induced apoptosis after ischemia-reperfusion in vitro involving translational suppression of the survival kinase PKB/ Akt (Akt), and elucidated an alternative protective role of antioxidants in the regulation of Akt activity. Using human choriocarcinoma JEG-3 cells, we found that sustained activation of ER stress by tunicamycin or thapsigargin exacerbated apoptosis in oxygen-glucose-deprived cells during reoxygenation. This was mediated via a reduction in phosphorylated Akt secondary to downregulation of protein translation rather than suppression of phosphorylation. Transient overexpression of wild-type Akt, but not kinase-dead Akt, in JEG-3 cells diminished tunicamycin-OGD reoxygenation-induced apoptosis. The antioxidants Trolox and Edaravone reduced apoptosis, but the protective effect of Trolox was abrogated by the PI3K inhibitor, LY294002. We speculate that sustained ER stress may contribute to the placental dysfunction seen in human pregnancy complications.-Yung, H-w., Korolchuk, S., Tolkovsky, A. M., Charnock-Jones, D. S., Burton, G. J. Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells. Keywordsunfolded protein response; placenta; oxidative stress; trophoblast; CHOP PLACENTAL OXIDATIVE STRESS has been postulated to be a key factor in the pathogenesis of human pregnancy complications such as intrauterine growth retardation and pre-eclampsia (1,2). We recently proposed that the cause of the stress is an ischemia-reperfusion type injury (3). Unlike in other organs, where ischemia-reperfusion injury is usually an isolated insult caused by pathological blockage or rupture of blood vessels attenuating oxygen and nutrient supply, in the placenta mild ischemia-reperfusion is likely to be a repetitive process. Maternal blood flow through the intervillous space of the placenta may fluctuate through three principal mechanisms: intrinsic contraction of the spiral arteries supplying the placenta, external 1Correspondence:

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Section: Discussionmentioning

confidence: 99%

“…Numerous studies have revealed that phosphorylation of eIF-2α is able to inhibit protein translation (34), and there was an increase of eIF-2α phosphorylation upon tunicamycin challenge during OGD reoxygenation (Fig. 4B, lane 4).…”

Section: Sustainable Er Stress During Ogd Reoxygenation Inhibits Akt mentioning

confidence: 93%

Endoplasmic reticulum stress exacerbates ischemia‐reperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells

Yung¹,

Korolchuk²,

Tolkovsky³

et al. 2006

FASEB j.

115

118

View full text Add to dashboard Cite

show abstract

“…Most forms of brain ischemia, including transient global, permanent focal, and transient focal, lead to protein synthesis inhibition (38). Protein synthesis gradually recovers in the majority of regions during reperfusion, and the rate of translational recovery is affected by the duration of ischemia (39). Cell death ensues in brain regions where protein synthesis fails to recover, such as the CA1 domain of the hippocampus, following relatively short global ischemia (39).…”

Section: Hypoxic Regulation Of Translation and Ischemic Diseasementioning

confidence: 99%

“…Protein synthesis gradually recovers in the majority of regions during reperfusion, and the rate of translational recovery is affected by the duration of ischemia (39). Cell death ensues in brain regions where protein synthesis fails to recover, such as the CA1 domain of the hippocampus, following relatively short global ischemia (39). The initial translation inhibition is caused by eIF2α phosphorylation.…”

Section: Hypoxic Regulation Of Translation and Ischemic Diseasementioning

confidence: 99%

Hypoxia-Induced Signaling in the Cardiovascular System

Simon

Liu

Barnhart

et al. 2008

Annu. Rev. Physiol.

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Low oxygen (O2) levels are a naturally occurring feature of embryonic development, adult physiology, and diseases such as those of the cardiovascular system. Although many responses to O2 deprivation are mediated by hypoxia-inducible factors (HIFs), researchers are finding a growing number of HIF-independent pathways that promote O2 conformance and hypoxia tolerance. Here, we describe HIF-independent responses and how they impact cardiovascular tissue homeostasis.

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“…Subsequent studies of initiation factors showed these were generally acute changes that did not correlate with the long-term TA of CA1. 53 We showed that mRNA granules correlated with long-term TA but that colocalization of ELAV proteins with mRNA granules correlated with the survival of CA3 neurons and translation of the stress protein HSP70, 13 suggesting a defect in postischemic mRNA regulation. A defect in mRNA regulation is also consistent with lack of translation of HSP70 protein in CA1 in spite of its copious transcription, 33,[54][55][56][57][58][59] which was also observed for stress mRNAs induced by the unfolded protein response.…”

Section: Mrna Dysfunction After Brain I/rmentioning

confidence: 79%

Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat

Wang

Anggraini

DeGracia

2016

J Cereb Blood Flow Metab

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Prolonged translation arrest correlates with delayed neuronal death of hippocampal CA1 neurons following global cerebral ischemia and reperfusion. Many previous studies investigated ribosome molecular biology, but mRNA regulatory mechanisms after brain ischemia have been less studied. Here we investigated the embryonic lethal abnormal vision/Hu isoforms HuR, HuB, HuC, and HuD, as well as expression of mRNAs containing adenine and rich uridine elements following global ischemia in rat brain. Proteomics of embryonic lethal abnormal vision immunoprecipitations or polysomes isolated from rat hippocampal CA1 and CA3 from controls or following 10 min ischemia plus 8 h of reperfusion showed distinct sets of mRNA-binding proteins, suggesting differential mRNA regulation in each condition. Notably, HuB, HuC, and HuD were undetectable in NIC CA1. At 8 h reperfusion, polysome-associated mRNAs contained 46.1% of ischemia-upregulated mRNAs containing adenine and rich uridine elements in CA3, but only 18.7% in CA1. Since mRNAs containing adenine and rich uridine elements regulation are important to several cellular stress responses, our results suggest CA1 is disadvantaged compared to CA3 in coping with ischemic stress, and this is expected to be an important contributing factor to CA1 selective vulnerability. (Data are available via ProteomeXchange identifier PXD004078 and GEO Series accession number GSE82146).Keywords Global brain ischemia and reperfusion, hippocampal CA1, adenine and rich uridine elements mRNA, embryonic lethal abnormal vision, mRNA regulation

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Acute and persistent protein synthesis inhibition following cerebral reperfusion

Cited by 38 publications

References 32 publications

Endoplasmic reticulum stress exacerbates ischemia‐reperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells

Endoplasmic reticulum stress exacerbates ischemia‐reperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells

Hypoxia-Induced Signaling in the Cardiovascular System

Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat

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