Hypoxia Inducible Factor

There are several proteins that belong to the hypoxia inducible factor (HIF) family. In addition, HIF is thought to function in both cytoprotection and the pathophysiology of several diseases [97,98]. This section will focus specifically on HIF-1 and its role in cytoprotection. HIF-1 is a heterodimeric transcription factor containing the subunits HIF-1 a and HIF-1(3 [97,98], In the context of this chapter, HIF-1 can be thought of as a major regulator of genes necessary for adaptation to hypoxia. The list of genes thought to be dependent on HIF-1 include genes for vascularization [99], energy metabolism [100], vascular tone [101], and erythropoiesis [102] (Table II). In addition, haem oxygenase-1 expression is, in part, dependent on HIF-1 activity [103],

The transcriptional activity of HIF-1 is primarily dependent on the intracellular level of the HIF-la subunit, which is in turn highly dependent on the rate of HIF-la protein degradation [97,98], Under conditions of normal oxygen tension, the HIF-la protein subunit undergoes ubiquitination and subsequent degradation by proteasome activity, thereby preventing formation of the HIF-la/HIF-ip heterodimer [104,105], In response to hypoxia, the HIF-1 a protein subunit is no longer degraded, thereby increasing intracellular levels of HIF-1 a protein and allowing formation of the HIF-la/HIF-ip heterodimer, which is then transcriptionally active and allows for the expression of HIF-1-dependent genes. The exact mechanism by which cells "sense" hypoxia and curtail the degradation of the HIF-1 a protein subunit is not fully understood, but likely involves inhibition of ubiquitination and is related to the von Hipple-Lindau tumour sup pressor protein [97,106,107].

The cytoprotective properties of HIF-1 relate primarily to the HIF-1 -dependent genes that allow for adaptation to hypoxia. For example, induction of the HIF-1 -dependent gene, erythropoietin, leads to increased production of red blood cells, thereby increasing the oxygen carrying capacity of blood in the setting of hypoxia. This type of cytoprotective response is particularly important, for example, in children with cyanotic heart disease. Another example involves the HIF-1-dependent gene, vascular endothelial growth factor (VEGF), which is a critical growth factor for the development of blood vessels. In tissues subjected to ischemia, such as the myocardium, expression of VEGF promotes the development of neovascularization as a potential means of increasing blood flow to the ischemic tissue [108]. Yet another role for HIF-1 involves HIF-1-dependent expression of inducible nitric oxide synthase (see below) and ischemic preconditioning of the myocardium [109,110].

The biological importance of HIF-1 has been further established in transgenic mice having targeted deletions of the HIF-1 a or HIF-1P subunit. Mice homozygous for deletion of either subunit (HIF-la -/- or HIF-lp -/-) die during embryogenesis secondary to insufficient vascular development [100,111]. In contrast, heterozygote animals (HIF-la +/-) seem to develop normally compared to wild-type animals. When exposed to hypoxia, however, heterozygote animals have an impairment in the classical responses and adaptations to hypoxia (e.g., blunted increase of haematocrit, blunted increase of right ventricular mass [112]).

In summary, HIF-1-dependent gene expression warrants classification as an endogenous cytoprotective mechanism by allowing for adaptation to cellular hypoxia, whether it be secondary to low oxygen tension per se or due to decreased blood flow (ischemia). While some of the aforementioned cytoprotective mechanisms (e.g., the heat shock response) allow for more immediate forms of cytoprotection, the cytoprotective responses and adaptations associated with HIF-1 activation are comparatively slower to develop. In addition, some of the responses induced by HIF-1 activation can be maladaptive/pathologic depending on duration of activation (e.g., the development of pulmonary hypertension in the setting of chronic hypoxia). Thus a greater understanding of HIF-1 regulation and activity will be necessary in order to manipulate HIF-1 activity as a therapeutic option. These options will include, depending on the therapeutic goals and clinical scenario, either augmenting HIF-1 activity (e.g., in ischemic tissues as a means of increasing vascularity) or blunting HIF-1 activity (e.g., as a means of preventing pulmonary hypertension in the setting of chronic hypoxia).

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