Hypoxia-inducible factors (HIFs) aretranscription factors that respond to decreases in availableoxygen in the cellular environment, orhypoxia.[1][2] They also respond to instances ofpseudohypoxia, such as thiamine deficiency.[3][4] Both hypoxia and pseudohypoxia leads to impairment ofadenosine triphosphate (ATP) production by the mitochondria.
The HIF transcriptional complex was discovered in 1995 byGregg L. Semenza and postdoctoral fellow Guang Wang.[5][6][7] In 2016,William Kaelin Jr.,Peter J. Ratcliffe andGregg L. Semenza were presented theLasker Award for their work in elucidating the role of HIF-1 in oxygen sensing and its role in surviving low oxygen conditions.[8] In 2019, the same three individuals were jointly awarded theNobel Prize in Physiology or Medicine for their work in elucidating how HIF senses and adapts cellular response to oxygen availability.[9]
HIF1α expression inhaematopoietic stem cells explains the quiescent nature ofstem cells[16] for being metabolically maintaining at a low rate so as to preserve the potency of stem cells for long periods in a life cycle of an organism.
The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells fromdifferentiating. However, hypoxia promotes theformation of blood vessels, and is important for the formation of avascular system inembryos and tumors. The hypoxia inwounds also promotes the migration ofkeratinocytes and the restoration of theepithelium.[17] It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.[18]
In general, HIFs are vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death.[19] HIF-1 has been shown to be vital tochondrocyte survival, allowing the cells to adapt to low-oxygen conditions within thegrowth plates ofbones. HIF plays a central role in the regulation of human metabolism.[20]
Nobel Prize in Physiology or Medicine 2019: How Cells Sense and Adapt to Oxygen Availability. Under normoxic conditions, Hif-1 alpha is hydroxylated at two proline residues. It then associates with VHL and is tagged with ubiquitin resulting in proteasomal degradation. Under hypoxic conditions, Hif-1 alpha translocates to the cell nucleus and associates with Hif-1 beta. This complex then binds to the HRE region of the DNA resulting in the transcription of genes that are involved in a multitude of processes including erythropoesis, glycolysis, and angiogenesis.
Inhibition of electron transfer in thesuccinate dehydrogenase complex due to mutations in theSDHB orSDHD genes can cause a build-up of succinate that inhibits HIF prolyl-hydroxylase, stabilizing HIF-1α. This is termedpseudohypoxia.
HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. These includeglycolysis enzymes, which allowATP synthesis in an oxygen-independent manner, andvascular endothelial growth factor (VEGF), which promotesangiogenesis. HIF-1 acts by binding to hypoxia-responsive elements (HREs) inpromoters that contain the sequence 5'-RCGTG-3' (where R is a purine, either A or G). Studies demonstrate that hypoxia modulateshistonemethylation and reprogramschromatin.[25] This paper was published back-to-back with that of 2019Nobel Prize in Physiology or Medicine winner for MedicineWilliam Kaelin Jr.[26] This work was highlighted in an independent editorial.[27]
It has been shown that muscleA kinase–anchoring protein (mAKAP) organized E3 ubiquitin ligases, affecting stability and positioning of HIF-1 inside its action site in the nucleus. Depletion of mAKAP or disruption of its targeting to the perinuclear (in cardiomyocytes) region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia. Thus, "compartmentalization" of oxygen-sensitive signaling components may influence the hypoxic response.[28]
The advanced knowledge of the molecular regulatory mechanisms of HIF1 activity under hypoxic conditions contrast sharply with the paucity of information on the mechanistic and functional aspects governingNF-κB-mediated HIF1 regulation under normoxic conditions. However, HIF-1α stabilization is also found in non-hypoxic conditions through an unknown mechanism. It was shown thatNF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure.siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. Finally, it was shown that, when endogenous NF-κB is induced byTNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner.[29] HIF-1 and HIF-2 have different physiological roles. HIF-2 regulateserythropoietin production in adult life.[30]
In normal circumstances after injury HIF-1a is degraded byprolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF-1a via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of Hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF-1a can either turn off, or turn on the key process of mammalian regeneration.[31][32] One such regenerative process in which HIF1A is involved is skin healing.[33] Researchers at theStanford University School of Medicine demonstrated that HIF1A activation was able to prevent and treat chronic wounds in diabetic and aged mice. Not only did the wounds in the mice heal more quickly, but the quality of the new skin was even better than the original.[34][35][36] Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described[37][38] and a rejuvenating effect on aged facial skin was demonstrated in patients.[39] HIF modulation has also been linked to a beneficial effect on hair loss.[40] The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physicianDominik Duscher and pharmacologistDominik Thor, makes use of this mechanism.[41] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.[42][43][44][45]
Several drugs that act as selectiveHIF prolyl-hydroxylase inhibitors have been developed.[46][47] The most notable compounds are:Roxadustat (FG-4592);[48]Vadadustat (AKB-6548),[49]Daprodustat (GSK1278863),[50]Desidustat (ZYAN-1),[51] andMolidustat (Bay 85-3934),[52] all of which are intended as orally acting drugs for the treatment ofanemia.[53] Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617,[54] YC-1,[55] IOX-2,[56] 2-methoxyestradiol,[57] GN-44028,[58] AKB-4924,[59]Bay 87-2243,[60] FG-2216[61] and FG-4497.[62] By inhibiting prolyl-hydroxylase enzyme, the stability of HIF-2α in the kidney is increased, which results in an increase in endogenous production oferythropoietin.[63] Both FibroGen compounds made it through to Phase II clinical trials, but these were suspended temporarily in May 2007 following the death of a trial participant taking FG-2216 from fulminanthepatitis (liver failure), however it is unclear whether this death was actually caused by FG-2216. The hold on further testing of FG-4592 was lifted in early 2008, after the FDA reviewed and approved a thorough response from FibroGen.[64] Roxadustat, vadadustat, daprodustat and molidustat have now all progressed through to Phase III clinical trials for treatment of renal anemia.[48][49][50]
In other scenarios and in contrast to the therapy outlined above, research suggests that HIF induction in normoxia is likely to have serious consequences in disease settings with a chronic inflammatory component.[65][66][67] It has also been shown that chronic inflammation is self-perpetuating and that it distorts the microenvironment as a result of aberrantly activetranscription factors. As a consequence, alterations in growth factor, chemokine, cytokine, and ROS balance occur within the cellular milieu that in turn provide the axis of growth and survival needed forde novo development of cancer and metastasis. These results have numerous implications for a number of pathologies whereNF-κB and HIF-1 are deregulated, includingrheumatoid arthritis and cancer.[68][69][70][71][72][73] Therefore, it is thought that understanding the cross-talk between these two key transcription factors, NF-κB and HIF, will greatly enhance the process of drug development.[29][74]
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