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Abstract Hypoxia‐inducible factors (HIFs) activate gene transcription in response to reduced O 2 availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel–Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.
The vascular system delivers oxygen and nutrients to every cell in the vertebrate organism. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of hypoxic/ischaemic vascular responses, driving transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis, arteriogenesis, and the mobilization and homing of bone marrow-derived angiogenic cells. This review will focus on the pivotal role of HIF-1 in vascular homeostasis, the involvement of HIF-1 in vascular diseases, and recent advances in targeting HIF-1 for therapy in preclinical models.
DNA methylation of cytosine residues is a well-studied epigenetic change, which regulates gene transcription by altering accessibility for transcription factors. Hypoxia is a pervasive stimulus that affects many physiological processes. The circulatory and respiratory systems adapt to chronic sustained hypoxia, such as that encountered during a high-altitude sojourn. Many people living at sea level experience chronic intermittent hypoxia (IH) due to sleep apnea, which leads to cardiovascular and respiratory maladaptation. This article presents a brief update on emerging evidence suggesting that changes in DNA methylation contribute to pathologies caused by chronic IH and potentially mediate adaptations to chronic sustained hypoxia by affecting the hypoxia-inducible factor (HIF) signaling pathway.
Hypoxia‐inducible factor 1 (HIF‐1) is a heterodimeric transcription factor composed of HIF‐1α and HIF‐1β subunits that functions as a master regulator of oxygen homeostasis. Oxygen‐dependent hydroxylation of HIF‐1α provides a mechanism that allows changes in oxygenation to be transduced to the nucleus, leading to changes in gene expression. Hypoxia‐inducible factor 1 plays critical roles in development, physiology and disease pathogenesis. Analyses of mice that are heterozygous for a null allele at the locus encoding the HIF‐1α subunit have demonstrated that partial deficiency of HIF‐1 is sufficient to impair multiple physiological responses to continuous and intermittent hypoxia.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to reduced O 2 availability in mammals, including angiogenesis, erythropoiesis, and glycolysis. HIF-1 activity is controlled by the O 2 -regulated expression of the HIF-1α subunit. Under nonhypoxic conditions, HIF-1α protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1α result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1α and that missense mutations increase HIF-1α expression under nonhypoxic conditions by blocking ubiquitination.
Cells are able to sense reduced oxygen tension and modulate the expression of specific genes in order to adapt to hypoxic conditions. In the carotid body and pulmonary neuroepithelial bodies a heme-containing nicotinamide-adenine dinucleotide phosphate oxidase-coupled potassium channel serves as an oxygen sensor. Membrane depolarization triggers an increase in intracellular calcium levels and cellular responses. Hemoproteins may also sense oxygen In non-depolarizable cells. Hypoxia signal transduction involves protein phosphorylation and is affected by cellular redox state. Src, Ras, Raf and MAP kinases have been implicated in some systems involving hypoxia signal transduction. Gene products that are induced by hypoxia include cytokines, metabolic enzymes, transcription factors, cellular redox regulators and protective proteins. Study of hypoxic activation of erythropoietin gene transcription identified a hypoxia-inducible enhancer and transcription factor HIF-1 (hypoxia-inducible factor 1). Recent evidence suggests that HIF-1 may regulate transcription of hypoxia-inducible genes in a variety of cell types in cooperation with other transcription factors and may play an important role in coupling signal transduction pathways to the transcriptional activation of hypoxia inducible genes.
Erythropoietin gene (EPO) expression is activated by tissue hypoxia in renal peritubular interstitial fibroblasts and, to a lesser extent, in hepatocytes and ito cells of the liver. A hypoxia-inducible enhancer spanning approximately 50 bp within the 3'-flanking region of the EPO gene is required for transcriptional activation in hypoxic cells. Hypoxia-inducible factor 1 is a basic helix-loop-helix protein that binds at the 5' end of the enhancer. The binding of hypoxia-inducible factor 1 is absolutely required for enhancer function. Hepatocyte nuclear factor 4 is an orphan receptor that binds at the 3' end of the enhancer. The binding of hepatocyte nuclear factor 4 augments hypoxia-inducible transcription mediated by the enhancer but is not absolutely required for enhancer function. Factors binding to the enhancer may interact synergistically with factors binding to the EPO promoter to activate transcription in hypoxic cells. Indirect evidence suggests that oxygen tension may be sensed by a hemoprotein. In one model, the putative hemoprotein adopts different conformational states depending on whether O2 is bound. Another model proposes that the hemoprotein converts O2 to H2O2. The protein tyrosine kinase c-Src, GTP-binding protein Ras, and MAP kinase signal pathways have been implicated in hypoxia signal transduction, but no direct evidence links these pathways to EPO transcriptional activation.
Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia‐inducible factor 1 (HIF‐1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF‐1α subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age‐dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF‐1‐dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft‐bearing mice with low‐dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF‐1 DNA‐binding activity, HIF‐1‐dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.
