Analysis of BH3-only proteins upregulated in response to oxygen/glucose deprivation in cortical neurons identifies Bmf but not Noxa as potential mediator of neuronal injury.
Stress signaling in response to oxygen/glucose deprivation (OGD) and ischemic injury activates a group of pro-apoptotic genes, the Bcl-2 homology domain 3 (BH3)-only proteins, which are capable of activating the mitochondrial apoptosis pathway. Targeted studies previously identified the BH3-only proteins Puma, Bim and Bid to have a role in ischemic/hypoxic neuronal injury. We here investigated the transcriptional activation of pro-apoptotic BH3-only proteins after OGD-induced injury in murine neocortical neurons. We observed a potent and early upregulation of noxa at mRNA and protein level, and a significant increase in Bmf protein levels during OGD in neocortical neurons and in the ipsilateral cortex of mice subjected to transient middle cerebral artery occlusion (tMCAO). Surprisingly, gene deficiency in noxa reduced neither OGD- nor glutamate-induced neuronal injury in cortical neurons and failed to influence infarct size or neurological deficits after tMCAO. In contrast, bmf deficiency induced significant protection against OGD- or glutamate-induced injury in cultured neurons, and bmf-deficient mice showed reduced neurological deficits after tMCAO in vivo. Collectively, our data not only point to a role of Bmf as a BH3-only protein contributing to excitotoxic and ischemic neuronal injury but also demonstrate that the early and potent induction of noxa does not influence ischemic neuronal injury.
The authors acknowledge the funding supported by Fundació Científica La Marató TV3 (111630/31) and SFI (08/IN.1/B1949). We wish to thank Professor Andreas Villunger for the generous gifts of the Bmf monoclonal antibody and plasmid; Professor Andreas Strasser and Professor Andreas Villunger for the bmf- and noxa-deficient mice; and Professor Eric Eldering for his help in the shipment of these mice.
CommentsThis article is also available at http://www.nature.com/cddis/journal/v5/n10/full/cddis2014426a.html
Published CitationPfeiffer S, Aniilkumar U, Chen G, Ramirez-Peinada S, Galindo-Moreno J, Munoz-Pinedo C, Prehn JH. Analysis of BH3-only proteins upregulated in response to oxygen/glucose deprivation in cortical neurons identifies Bmf but not Noxa as potential mediator of neuronal injury. Cell Death and Disease. 2014;5:e1456
- Physiology and Medical Physics