Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein following focal cerebral ischemia in rats.

Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in cells. In this study, we reported an early, time-related, gradual up-regulation of HIF-1alpha, and a moderate increase in vascular endothelial growth factor (VEGF)- and erythropoietin (Epo)-levels following transient focal ischemia. Moreover, we demonstrated, for the first time a specific localization of the pro-apoptotic regulator BNIP3 in striatal and cortical neurons after transient focal ischemia in rats. Prolonged intranuclear BNIP3 immunoreactivity was associated with delayed neuronal death. Experiments showed protein increases on Western blots of brain tissue with peaks at 48h after ischemia. Epo responds to ischemia in an early stage, whereas VEGF and BNIP3 accumulate in cells at later times after ischemia. This suggests the possibility that BH3-only proteins might be one of the major downstream effectors of HIF-1alpha in hypoxic cell death. These findings open the possibility that the hypoxia-regulated pro-apoptotic protein BNIP3 enters the nucleus and could interact with other proteins involved in DNA structure, transcription or mRNA splicing after focal brain ischemia.

Althaus J ，Bernaudin M ，Petit E ，Toutain J ，Touzani O ，Rami A ... -  《NEUROCHEMISTRY INTERNATIONAL》

Effects of transient focal cerebral ischemia in mice deficient in puma.

Bcl-2 homology domain 3 (BH3)-only pro-apoptotic proteins may play an important role in upstream cell death signaling pathways underlying ischemic brain injury. Puma is a potent BH3-only protein that can be induced via p53, FoxO3a and endoplasmic reticulum stress pathways and is upregulated by global cerebral ischemia. To more completely define the contribution of Puma to ischemic brain injury we measured the expressional response of Puma to transient focal cerebral ischemia in mice and also compared infarct volumes in puma-deficient versus puma-expressing mice. Real-time quantitative PCR determined puma mRNA levels were significantly increased 8h after 90min middle cerebral artery (MCA) occlusion in the ipsilateral cortex, while expression remained unchanged contralaterally. Puma protein levels were also increased in the ischemic cortex over the same period. However, cortical and striatal infarct volumes were not significantly different between puma-deficient and puma-expressing mice at 24h, and no differences between genotypes were found for post-ischemic neurological deficit scores. These data demonstrate that focal cerebral ischemia is associated with puma induction but suggest that Puma does not contribute significantly to lesion development in the present model.

Kuroki K ，Virard I ，Concannon CG ，Engel T ，Woods I ，Taki W ，Plesnila N ，Henshall DC ，Prehn JH ... -  《NEUROSCIENCE LETTERS》

Nuclear localization of the hypoxia-regulated pro-apoptotic protein BNIP3 after global brain ischemia in the rat hippocampus.

Schmidt-Kastner R ，Aguirre-Chen C ，Kietzmann T ，Saul I ，Busto R ，Ginsberg MD ... -  《BRAIN RESEARCH》

[Relationship between hypoxia-inducible factor-1alpha expression and extracellular signal-regulated kinase in hypoxic-ischemic cortical neurons].

Zhang L ，Qu Y ，Zhang X ，Yang C ，Mao M ，Mu D ... -  《-》

HIF-1alpha reveals a binding activity to the promoter of iNOS gene after permanent middle cerebral artery occlusion.

Matrone C ，Pignataro G ，Molinaro P ，Irace C ，Scorziello A ，Di Renzo GF ，Annunziato L ... -  《JOURNAL OF NEUROCHEMISTRY》