HIF-1alpha cytoplasmic accumulation is associated with cell death in old rat cerebral cortex exposed to intermittent hypoxia.
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 1alpha (HIF-1alpha)--the master regulator of oxygen homeostasis--concomitant with p66(Shc) activation and reduced IkBalpha 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-1alpha levels, combined with a low level of IkBalpha 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-1alpha activation in cortical neurons may produce rescue proteins in response to intermittent hypoxia.
Rapino
Cinzia
C
Dipartimento di Scienze Biomediche, Facoltà di Farmacia, Università G. d'Annunzio, 66100 Chieti-Pescara, Italy.
Bianchi
Giuseppina
G
Di Giulio
Camillo
C
Centurione
Lucia
L
Cacchio
Marisa
M
Antonucci
Adriano
A
Cataldi
Amelia
A
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008859:Microscopy, Polarization; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors