Hypoxia refers to a condition in which oxygen is limited. It is mainly related to pathological situations, but it can also be a part of normal physiology. Hypoxia activates the hypoxia signaling pathway, which is predominantly regulated by hypoxia-inducible factor (HIF) stabilization. Hypoxia-inducible factor (HIF) 1-alpha is a ubiquitously expressed, master regulator of genes that allow adaptation to hypoxic conditions. Target genes include VEGF, erythropoietin, glycolytic enzymes, glucose transporters, and other factors critical to vascularization, metabolic regulation, cell multiplication and survival.


In normoxic conditions, the proline residues of HIF-α subunits are hydroxylated by oxygen-dependent prolyl-4-hydroxylases (PHDs). Von Hippel–Lindau protein (pVHL), an E3 ubiquitin ligase, binds to the hydroxylated HIF-α and acts as a substrate recognition component of the E3 ubiquitin ligase complex, which leads to the proteosomal degradation of HIF protein. The asparagine residues of HIF-α subunits are also hydroxylated by factors inhibiting HIFs (FIHs), which inhibits the binding of HIF with co-activators p300/CREB-binding protein. This is how HIF activity is kept to a minimum during normal conditions.

However under hypoxia, the activity of PHDs and FIHs are suppressed, and HIF-α subunits translocate into the nucleus to bind with the constitutively-expressed HIF-β subunit as well as the transcriptional co-activator p300/CBP. The resulting protein complex binds to regulatory regions called hypoxia response elements (HREs), which leads to expression of downstream genes. HIF activity can also be controlled indirectly, either through activation of HIF-α mRNA transcription or regulation of HIF-α protein synthesis. The former is achieved either through NF-κB signaling or the Jak-Stat3 pathway, while the latter occurs via PI3K/Akt/mTOR pathway. Either of these processes results in upregulation of HIF-α, promoting cell survival in hypoxic conditions. All of these studies support the notion that hypoxia and inflammation have an interdependent relationship. In fact, many studies demonstrate that although hypoxia can cause tissue inflammation, stabilization of HIF can dampen tissue inflammation and promote its repair.

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