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

详细信息    查看全文

• 作者：Peppi Koivunen ; ^{peppi.koivunen@oulu.fi} ; Raisa Serpi ; Elitsa Y. Dimova
• 关键词：Atherosclerosis ; Cardioprotection ; Hypoxia-inducible factor (HIF) ; HIF prolyl 4-hydroxylases (HIF-P4Hs) ; Metabolic syndrome ; Obesity
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：114
• 期：Complete
• 页码：265-273
• 全文大小：1727 K
• 卷排序：114

文摘

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.