The roles of HIF-1α 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 hypoxiaresponsive genes. The HIF-a 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 cardiovascular 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. It binds to hemoglobin and is distributed to all organs in the body. In cardiovascular diseases and anemia, the drop in local oxygen levels causes tissue hypoxia and triggers the expression of hypoxia-responsive genes. Hypoxia-inducible factors (HIFs) regulate these genes, and their degradation is inhibited under hypoxic conditions. HIF-alpha proteins form complexes with HIF-1 beta, leading to the activation of hypoxia-responsive genes. HIF-alpha signaling is a potential target for treating renal anemia, and HIF-PH inhibitors are used to restore EPO production. This review focuses on the role of HIF-alpha signaling in cardiovascular diseases, including its impact on cardiomyocytes and stromal cells such as macrophages.