Bax shuttling after neonatal hypoxia-ischemia: Hyperoxia effects

Martin B. Gill, Kurt Bockhorst, Ponnada Narayana, J. Regino Perez-Polo

    Research output: Contribution to journalArticle

    35 Citations (Scopus)

    Abstract

    Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O2 resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O2 (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1β) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O2 resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O2 treatment for neonatal HI should be reevaluated.

    Original languageEnglish (US)
    Pages (from-to)3584-3604
    Number of pages21
    JournalJournal of Neuroscience Research
    Volume86
    Issue number16
    DOIs
    StatePublished - 2008

    Fingerprint

    bcl-2-Associated X Protein
    Hyperoxia
    Ischemia
    Cell Death
    Endoplasmic Reticulum
    Resuscitation
    Organelles
    Caspase 12
    Poly Adenosine Diphosphate Ribose
    Phenotype
    Calpain
    Live Birth
    Nuclear Proteins
    Hypoxia
    Interleukin-1
    Caspase 3
    Mitochondria
    Proteins
    Therapeutics
    Magnetic Resonance Imaging

    Keywords

    • Apoptosis
    • Bax
    • Hyperoxia
    • Hypoxia-ischemia
    • Inflammation
    • Necrosis

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience

    Cite this

    Gill, M. B., Bockhorst, K., Narayana, P., & Perez-Polo, J. R. (2008). Bax shuttling after neonatal hypoxia-ischemia: Hyperoxia effects. Journal of Neuroscience Research, 86(16), 3584-3604. https://doi.org/10.1002/jnr.21795

    Bax shuttling after neonatal hypoxia-ischemia : Hyperoxia effects. / Gill, Martin B.; Bockhorst, Kurt; Narayana, Ponnada; Perez-Polo, J. Regino.

    In: Journal of Neuroscience Research, Vol. 86, No. 16, 2008, p. 3584-3604.

    Research output: Contribution to journalArticle

    Gill, MB, Bockhorst, K, Narayana, P & Perez-Polo, JR 2008, 'Bax shuttling after neonatal hypoxia-ischemia: Hyperoxia effects', Journal of Neuroscience Research, vol. 86, no. 16, pp. 3584-3604. https://doi.org/10.1002/jnr.21795
    Gill, Martin B. ; Bockhorst, Kurt ; Narayana, Ponnada ; Perez-Polo, J. Regino. / Bax shuttling after neonatal hypoxia-ischemia : Hyperoxia effects. In: Journal of Neuroscience Research. 2008 ; Vol. 86, No. 16. pp. 3584-3604.
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