The roles of HIF-1? signaling in cardiovascular diseases

Oxygen is essential for living organisms. Molecular oxygen binds to hemoglobin and is delivered to every organ in the body. In several cardiovascular diseases or anemia, local oxygen tension drops below its physiological level and tissue hypoxia develops. In such conditions, the expression of hypoxia-responsive genes increases to alleviate the respective condition. The hypoxia-responsive genes include the genes coding erythropoietin (EPO), vascular endothelial growth factor-A, and glycolytic enzymes. Hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha, and HIF-3 alpha are transcription factors that regulate the hypoxia-responsive genes. The HIF-alpha proteins are continuously degraded by an oxygen-dependent degrading pathway involving HIF-prolyl hydroxylases (HIF-PHs) and von Hippel-Lindau tumor suppressor protein. However, upon hypoxia, this degradation ceases and the HIF-alpha proteins form heterodimers with HIF-1 beta (a constitutive subunit of HIF), which results in the induction of hypoxia responsive genes. HIF-1 alpha and HIF-2 alpha are potential therapeutic targets for renal anemia, where EPO production is impaired due to chronic kidney diseases. Small molecule HIF-PH inhibitors are currently used to activate HIF-alpha signaling and to increase plasma hemoglobin levels by restoring EPO production. In this review, we will discuss the current understanding of the roles of the HIF-alpha signaling pathway in cardio-vascular diseases. This will include the roles of HIF-1 alpha in cardiomyocytes as well as in stromal cells including macrophages.(c) 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Automated summary

Oxygen is vital for living organisms as it binds to hemoglobin and is transported throughout the body. In conditions of cardiovascular diseases or anemia, the local oxygen levels decrease and tissue hypoxia occurs, leading to the upregulation of hypoxia-responsive genes. These genes include erythropoietin (EPO), vascular endothelial growth factor-A, and glycolytic enzymes. Hypoxia-inducible factors (HIF) such as HIF-1 alpha and HIF-2 alpha play crucial roles in regulating these genes, and their degradation is halted during hypoxia. HIF-alpha signaling pathway has therapeutic potential in renal anemia, and small molecule HIF-PH inhibitors are employed to restore EPO production.