Persisting mild hypothermia suppresses hypoxia-inducible factor 1alpha protein synthesis and HIF-1-mediated gene expression
- ISSN: 15221490
- ISBN: 007322009p
Abstract
The transcription factor hypoxia-inducible factor 1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia/ischemia. Ischemia makes the tissue not only to be hypoxic but also to be hypothermic because of the hypoperfusion under certain circumstances. On the other hand, the induced hypothermia is one of the most common therapeutic modalities to extend tolerance to hypoxia. Although hypoxia elicits a variety of cellular and systemic responses at different organizational levels in the body, little is known about how hypoxia-induced responses are affected by low temperature. We examined the influence of mild hypothermic conditions (28-32 degrees C) on HIF-1 in both in vitro and in vivo settings. In vitro experiments adopting cultured cells elucidated that hypoxia-induced HIF-1 activation was resistant to 4h-exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent up-regulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1alpha protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracelluar ATP content was reduced under 1% O2 conditions but was not largely affected by hypothermic treatment. The evidence indicate that reduction of oxygen consumption is not largely involved in suppression of HIF-1. In addition, we demonstrated that HIF-1 DNA binding activity and HIF-1-depenedent gene expressions induced under 10% O2 atmosphere in mice brain were not influenced by treatment under 3 h-hypothermic temperature but inhibited under 5 h-treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. Here we describe first time that persisting low temperature significantly reduced HIFalpha neosynthesis under hypoxic conditions, leading to decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings. Key words: hypoxia, hypothermia, hypoxia-inducible factor 1, ischemia.
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