HIF-1α cytoplasmic accumulation is associated with cell death in old rat cerebral cortex exposed to intermittent hypoxia

Abstract

Intermittent hypoxia, followed by reoxygenation, determines the production of reactive oxygen species (ROS), which may lead to accelerated aging and to the appearance of age-related diseases. The rise in ROS levels might constitute a stress-stimulus activating specific redox-sensitive signalling pathways, so inducing either damaging or protective functions. Here, we report that in old rat cerebral cortex exposed to hypoxia, the accumulation in the cytoplasm of hypoxic inducible factor 1α (HIF-1α)-the master regulator of oxygen homeostasis - concomitant with p66Shc activation and reduced IkBα phosphorylation is associated with tissue apoptosis or necrosis. In young cerebral cortex, we hypothesize that the hypoxic damage may be reversible, based on our demonstration of elevated HIF-1α levels, combined with a low level of IkBα phosphorylation, a decrease in IAP-1 and a lack of major change in Bcl2 family proteins. These observations are associated with a low level of cell death induced by hypoxia, suggesting that HIF-1α activation in cortical neurons may produce rescue proteins in response to intermittent hypoxia. © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2005.