Hypoxia-inducible factor prolyl 4-hydroxylase inhibition in cardiometabolic diseases.
Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also called PHDs and EglNs) are enzymes that act as cellular oxygen sensors. They are the main downregulators of the hypoxia-inducible factor (HIF). HIF-P4Hs can be targeted with small molecule inhibitors, which stabilize HIF under normoxia and initiate the hypoxia response. Such inhibitors are in phase 2 and 3 clinical trials for the treatment of anemia due to their ability to induce erythropoietin and iron metabolism genes. Recent data suggest that HIF-P4H inhibition has a therapeutic role beyond anemia in cardiac ischemia, obesity and metabolic dysfunction, and atherosclerosis. The molecular level mechanisms involved are HIF stabilization driven changes in gene expression that improve perfusion and endothelial function, reprogram metabolism to promote glucose intake and glycolysis over oxidative metabolism, reduce inflammation and beneficially modify innate immune system. This review discusses the recent findings in detail.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine and Oulu Center for Cell-Matrix Research, University of Oulu, Finland. Electronic address: peppi.koivunen@oulu.fi.
Peppi
P
Koivunen
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine and Oulu Center for Cell-Matrix Research, University of Oulu, Finland.
Raisa
R
Serpi
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine and Oulu Center for Cell-Matrix Research, University of Oulu, Finland.
Elitsa Y
EY
Dimova
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D051793:Hypoxia-Inducible Factor 1; D064800:Prolyl-Hydroxylase Inhibitors; D064828:Prolyl Hydroxylases
Atherosclerosis; Cardioprotection; HIF prolyl 4-hydroxylases (HIF-P4Hs); Hypoxia-inducible factor (HIF); Metabolic syndrome; Obesity