HIF/HIF Prolyl-Hydroxylase

HIF/HIF Prolyl-Hydroxylase

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. HIF prolyl-hydroxylase is an enzyme involved in the HIF (Hypoxia-inducible factor) signalling pathways, and is the target for a set of therapeutic drugs called HIF prolyl-hydroxylase inhibitors.

An Overview of HIF/HIF Prolyl-Hydroxylase

Hypoxia-inducible factor (HIF) is the center of cellular perception and adaptation to regulatory factors of oxygen levels. HIF is the most important transcription factor family involved in hypoxia response, and regulates the expression of multiple genes, which is closely related to the normal physiological regulation and some pathological processes of the organism. HIF has a comprehensive regulatory capacity, as from 1995 as a target to 2009 preclinical research being completed, people have found that HIF can regulate a variety of gene transcription.

Major types of HIF/HIF Prolyl-Hydroxylase

The HIF family currently includes 3 members: HIF-1, HIF-2 and HIF-3. HIF-α includes 3 members: HIF-1α, HIF-2α and HIF-3α. HIF-1α and HIF-2α are more deeply studied among them. HIF-1α and HIF-2α proteins are conserved in protein sequences and structures, with 48% of protein sequences similar to the same structural domains. HIF-3α can produce many different protein isomers due to variable splicing. In addition, HIF-3α interacts with HIF-1β as well as HIF-1α and HIF-2α. HIF-3α plays a negative role in HIF-1β and HIF-1α by competitive combination of HIF-2α as the dominant negative factor.

Inhibition of HIF/HIF Prolyl-Hydroxylase

HIF prolyl-hydroxylase is a kind of enzyme involving in HIF signaling pathway, which is a target of therapeutic drugs called HIF hydroxyproline inhibitors. When inhibiting the activity of proline-hydroxylase, it can reduce the degradation of HIF and promote the hematopoiesis of organism. When the oxygen partial pressure is normal, the HIF-α is rapidly degraded. When the oxygen partial pressure drops, the HIF is reduced, the HIF-α is no longer degraded and transferred to the nucleus and the HIF-β forms the dimer and activates the gene transcription.

HIF/HIF Prolyl-Hydroxylase and diseases

HIF-1 is associated with acute kidney injury (AKI) and chronic kidney disease (CKD) and other diseases. During the long period of hypoxia, the expression of HIF-1 in the lung epithelial cells decreased with the prolongation of hypoxia time, but the expression of HIF-2 was elevated, which was related to the mechanism of tumor disease. HIF can stimulate the production of kidney and liver erythropoietin, thus regulating and coordinating various levels of red blood cell generation, so stabilizing hif can treat renal anemia.

References:

1. Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S & Haase, V. H. (2007). Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo.The Journal of clinical investigation,117(4), 1068-1077.

2. Bernhardt, W. M., Wiesener, M. S., Scigalla, P., Chou, J., Schmieder, R. E., Günzler, V., & Eckardt, K. U. (2010). Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.Journal of the American Society of Nephrology, ASN-2010010116.

3. Choudhry, H., & Harris, A. L. (2017). Advances in hypoxia-inducible factor biology.Cell metabolism.

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