HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review

Abstract

Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors.

Gene Expression Profile of Human Mesenchymal Stromal Cells Exposed to Hypoxic and Pseudohypoxic Preconditioning—An Analysis by RNA Sequencing

“…Lastly, we would like to mention that the clinical use of PHDs inhibitors often raises concerns about their potential effects in promoting tumorigenesis, even though clinical trials generally do not confirm an increased incidence of cancer in treated patients (reviewed in [ 35 ]). While analysis of the list of differentially expressed genes between Vadadustat preconditioning and control cells using the KEGG database indicated upregulation of 9 genes associated with renal cell carcinoma and 10 genes associated with colorectal cancer, this was not surprising as it was already known that the HIF-1 pathway is upregulated in these two types of cancer [ 36 , 37 ].…”

Sodium–Glucose Cotransporter 2 Inhibitors Work as a “Regulator” of Autophagic Activity in Overnutrition Diseases

“…HIFs are transcription factors that respond to hypoxia. In normal circumstances, HIF-α is constantly synthesized but degraded by prolyl hydroxylases (PHDs), so intracellular concentration of HIF-α is kept low ( Hirota, 2021 ). Under hypoxic conditions, PHDs are inactivated and HIF-α translocates into the nucleus, binds to HIF-1β, and then forms heterodimer ( Hirota, 2021 ).…”

“…In normal circumstances, HIF-α is constantly synthesized but degraded by prolyl hydroxylases (PHDs), so intracellular concentration of HIF-α is kept low ( Hirota, 2021 ). Under hypoxic conditions, PHDs are inactivated and HIF-α translocates into the nucleus, binds to HIF-1β, and then forms heterodimer ( Hirota, 2021 ). The heterodimer of HIFs then binds to the hypoxia-responsive element (HRE) region of the DNA, resulting in the transcription of genes that are involved in the response to hypoxia conditions ( Hirota, 2021 ).…”

“…Under hypoxic conditions, PHDs are inactivated and HIF-α translocates into the nucleus, binds to HIF-1β, and then forms heterodimer ( Hirota, 2021 ). The heterodimer of HIFs then binds to the hypoxia-responsive element (HRE) region of the DNA, resulting in the transcription of genes that are involved in the response to hypoxia conditions ( Hirota, 2021 ). The HIF-α family consists of HIF-1α, HIF-2α, and HIF-3α.…”

Special Issue: Hypoxia-Inducible Factors: Regulation and Therapeutic Potential

“…inhibiting HIF-PH, and the significance and implications of medical intervention using HIF-PH inhibitors [15].…”