HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity.
2-oxoglutarate oxygenase inhibitor
Roxadustat
anemia
hypoxia
prolyl hydroxylase inhibitor
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
02
09
2019
revised:
13
11
2019
accepted:
27
11
2019
pubmed:
8
1
2020
medline:
29
9
2020
entrez:
8
1
2020
Statut:
ppublish
Résumé
Pharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIH-selective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO
Identifiants
pubmed: 31908020
doi: 10.1096/fj.201902240R
doi:
Substances chimiques
Enzyme Inhibitors
0
EGLN3 protein, human
EC 1.14.11.29
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2344-2358Subventions
Organisme : British Heart Foundation
ID : PG/12/33/29546
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
© 2019 Federation of American Societies for Experimental Biology.
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