Hypoxia-inducible factor prolyl 4-hydroxylase inhibition in cardiometabolic diseases

• Published in: Pharmacological research 2016-12, Vol.114, p.265-273
• Main Authors: Koivunen, Peppi, Serpi, Raisa, Dimova, Elitsa Y.
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis; Cardioprotection; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - metabolism; HIF prolyl 4-hydroxylases (HIF-P4Hs); Humans; Hypoxia-inducible factor (HIF); Hypoxia-Inducible Factor 1 - metabolism; Metabolic Diseases - drug therapy; Metabolic Diseases - metabolism; Metabolic syndrome; Obesity; Prolyl Hydroxylases - metabolism; Prolyl-Hydroxylase Inhibitors - pharmacology; Prolyl-Hydroxylase Inhibitors - therapeutic use
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2016.11.003

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.