HIF-dependent genes

Strategies are now being developed to use hypoxia-inducible promoters for applications in gene therapy (Rinsch et al., 1997 Shibata et al., 2000). Hypoxia provides not only a means of inducing HIF-dependent promoters, but also a means of selective expression in a pathophysiological state. 

List of Abbreviations HIF, hypoxia-inducible factor HREs, hypoxia response elements Hsps, heat-shock proteins iNOS, inducible nitric oxide synthase NE, noradrenabne ODG, oxygen-dependent genes ROS, reactive oxygen species TH, tyrosine hydroxylase... 

Shock-dependent initialising mechanisms cause the induction of iNOS, COX-2, and CD 14. The early response genes, iNOS and COX-2, promote the inflammatory response by the rapid and excessive production of NO and prostaglandins. The transcription factor hypoxia-inducible factor-1 (HIF-1) may also regulate the induction of iNOS during the ischemic phase of shock, contributing to the excess NO formation. 

Both NO and CO may affect (and be involved in) oxygen-dependent phenomena. Accordingly, in vitro experiments have demonstrated that elevated levels of NO or CO can diminish effects of hypoxia on gene transcription. These molecules both activated the internal oxygen-dependent degradation domain and repressed the C-terminal transactivation domain of HIF resulting in less HIF-la that can bind to DNA (Huang et al., 1999). On the other hand, in vivo experiments have demonstrated that NO is one of the modulators of the hypoxic ventilatory response mediated by the rostral mediolateral medulla (de Paula and Branco, 2003). It is not clear at present, whether different cell types respond in a different manner. 

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