title: The Hypothermic Influence on CHOP and Ero1-α in an Endoplasmic Reticulum Stress Model of Cerebral Ischemia.
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.
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. gagandipkb@hotmail.com.
authors.forename: Gagandip K
authors.initials: GK
authors.lastname: Poone
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. henrik.hasseldam@bric.ku.dk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasseldam
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. nmunkholm@hotmail.com.
authors.forename: Nina
authors.initials: N
authors.lastname: Munkholm
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. rsr@sund.ku.dk.
authors.forename: Rune S
authors.initials: RS
authors.lastname: Rasmussen
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. ninavg@sund.ku.dk.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Grønberg
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Denmark. ffj@sund.ku.dk.
authors.forename: Flemming F
authors.initials: FF
authors.lastname: Johansen
keywords: Ero1-α protein; brain ischemia; hypoxia-inducible factor-proline dioxygenases; stroke; transcription factor CHOP; unfolded protein response