A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). HIF-1, composed of a dimer of an alpha (HIF-1α) and a beta (ARNT or HIF-1β) subunit, is present in all nucleated cells of metazoan organisms. The subunits of HIF-1 bind together to acquire transcriptional properties, allowing it to regulate the transcriptional activity of hundreds of genes that promote cell survival in hypoxic conditions. Considered to be a master regulator of oxygen homeostasis, HIF-1 acts predominantly under hypoxic conditions. The HIF-1β subunit is constitutively expressed whereas the HIF-1α subunit is oxygen regulated. Regulation of HIF-1 is thus determined by the rapid posttranslational degradation or stabilization of the HIF-1α subunit.In normal tissue oxygen conditions, HIF-1α is rapidly and continuously degraded following translation. Tissue hypoxia, however, induces a sustained increase in the expression of HIF-1α.
Adaptive cellular responses to hypoxia are mediated by HIF-1, which upregulates the expression of many genes that enhance healing in low-oxygen conditions. HIF-1 activation is also a primary stimulus of angiogenesis, the formation of new blood vessels from pre-existing vessels, in both physiological and pathological conditions. Hypoxia stimulates the growth and remodeling of the existing vasculature. This enhances blood flow to oxygen-deprived tissues through the activation of several HIF target genes. These include vascular endothelial growth factor (VEGF), a potent angiogenic factor, as well as other angiogenic growth factors, such as angiopoietin 2 and stromal cell-derived factor 1 (SDF-1).
In vivo microenvironment for hematopoietic stem cells is hypoxic, and stabilized HIF-1α is required to maintain their stem cell-like properties. Mesenchymal stem cells cultured at an oxygen concentration of 3% showed delayed replicative senescence compared with cells cultured in ambient atmospheric conditions of ~20% O2. It has also been shown that aged cells display a decreased ability to express HIF-1 target genes under hypoxic conditions and impaired binding of HIF-1 to HREs. These observations may explain the susceptibility of aged organisms to hypoxic stress. Together these findings suggest that oxygen limitation and/or activation of HIF-1 play important roles in cellular senescence. Three independent studies have shown that stabilization of HIF-1 can increase life span, while three studies have found that deletion of hif-1 can increase life span. There seems to be consensus that life span extension from stabilization of HIF-1 depends on a mechanism. One possible explanation for HIF-1 mediated lifespan extension is that HIF-1 down-regulates mitochondrial activity. Alternatively, HIF-1 could act as a stress response factor to up-regulate protection against multiple stresses.