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

• Published in: Neurochemistry international 2006-06, Vol.48 (8), p.687-695
• Main Authors: Althaus, J, Bernaudin, M, Petit, E, Toutain, J, Touzani, O, Rami, A
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - genetics; Animals; Apoptosis - genetics; Brain Ischemia - genetics; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cerebral Cortex - metabolism; Cerebral Cortex - physiopathology; Cerebral Infarction - genetics; Cerebral Infarction - metabolism; Cerebral Infarction - physiopathology; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Disease Models, Animal; Erythropoietin - metabolism; Gene Expression Regulation - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Infarction, Middle Cerebral Artery - genetics; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - physiopathology; Life Sciences; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mitochondrial Proteins; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurons - metabolism; Neurons and Cognition; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Rats, Wistar; Signal Transduction - genetics; Time Factors; Up-Regulation - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0197-0186; 0197-0186

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.