Persisting mild hypothermia suppresses hypoxia-inducible factor-1alpha protein synthesis and hypoxia-inducible factor-1-mediated gene expression
| Autor: | Seiko Oda, Takehiko Adachi, Kazuhiko Fukuda, Takuhiko Wakamatsu, Hiroki Daijo, Shinae Kizaka-Kondoh, Shinichi Kai, Tomoharu Tanaka, Kiichi Hirota |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Hypoxia-Inducible Factor 1 Pathology medicine.medical_specialty Physiology Ischemia Hypothermia Biology AMP-Activated Protein Kinases Severity of Illness Index Mice Physiology (medical) Cell Line Tumor Gene expression medicine Animals Humans Phosphorylase a Hypoxia Transcription factor Mice Inbred BALB C Ribosomal Protein S6 Brain Neoplasms Temperature Brain Hypoxia (medical) medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Cell biology Hindlimb Disease Models Animal Hypoxia-inducible factors Gene Expression Regulation Cell culture medicine.symptom Glioblastoma Acetyl-CoA Carboxylase |
| Zdroj: | American journal of physiology. Regulatory, integrative and comparative physiology. 298(3) |
| ISSN: | 1522-1490 |
| Popis: | The transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia-ischemia. Ischemia causes 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°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 4-h exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent upregulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1α protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracellular ATP content was reduced under 1% O2 conditions but was not largely affected by hypothermic treatment. The evidence indicates 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-dependent gene expressions induced under 10% O2 atmosphere in mouse brain were not influenced by treatment under 3-h hypothermic temperature but were inhibited under 5-h treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. In this report we describe for the first time that persisting low temperature significantly reduced HIF-1α neosynthesis under hypoxic conditions, leading to a decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings. |
| Databáze: | OpenAIRE |
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