Abstract
Hypoxia induced endoplasmic reticulum stress causes accumulation of unfolded proteins in the endoplasmic reticulum and activates the unfolded protein response, resulting in apoptosis through CCAAT-enhancer-binding protein homologous protein (CHOP) activation. In an in vitro and in vivo model of ischemic stroke, we investigated whether hypothermia regulates the unfolded protein response of CHOP and Endoplasmic reticulum oxidoreductin-α (Ero1-α), because Ero1-α is suggested to be a downstream CHOP target. The gene expression of CHOP and Ero1-α was measured using Quantitative-PCR (Q-PCR) in rat hippocampi following global cerebral ischemia, and in hypoxic pheochromocytoma cells during normothermic (37 °C) and hypothermic (31 °C) conditions. As a result of ischemia, a significant increase in expression of CHOP and Ero1-α was observed after three, six and twelve hours of reperfusion following global ischemia. A stable increase in CHOP expression was observed throughout the time course (p < 0.01, p < 0.0001), whereas Ero1-α expression peaked at three to six hours (p < 0.0001). Induced hypothermia in hypoxia stressed PC12 cells resulted in a decreased expression of CHOP after three, six and twelve hours (p < 0.0001). On the contrary, the gene expression of Ero1-α increased as a result of hypothermia and peaked at twelve hours (p < 0.0001). Hypothermia attenuated the expression of CHOP, supporting that hypothermia suppress endoplasmic reticulum stress induced apoptosis in stroke. As hypothermia further induced up-regulation of Ero1-α, and since CHOP and Ero1-α showed differential regulation as a consequence of both disease (hypoxia) and treatment (hypothermia), we conclude that they are regulated independently.
Highlights
Hypothermia is a promising treatment strategy following several medical conditions such as traumatic brain injury, myocardial infarction, cardiac arrest, and ischemic stroke [1,2,3,4]
Similar to CCAAT-enhancer-binding protein homologous protein (CHOP), Endoplasmic reticulum oxidoreductin-α (Ero1-α) was increased at 3 to 6 h following ischemia (p < 0.0001), it seemed to reach maximum at this time point and was reduced towards normal levels after 12 h of reperfusion
3, 6 and 12 h after ischemic injury all show significant up-regulation of Ero1-α compared to untreated controls (p < 0.0001 and 0.01 respectively)
Summary
Hypothermia is a promising treatment strategy following several medical conditions such as traumatic brain injury, myocardial infarction, cardiac arrest, and ischemic stroke [1,2,3,4]. The benefits of therapeutic cooling have been demonstrated in several experimental in vitro and in vivo studies of cerebral ischemia [5,6,7,8,9]. Overall, these investigations found improvements in metabolism, inhibition of inflammatory mediators, regulation of gene expression, improved blood brain barrier (BBB) integrity, and regulation of the balance between cell death and survival following an ischemic stroke. In response to cellular aggregation of misfolded and/or unfolded proteins, the Unfolded Protein Response (UPR)
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