Hypoxia occurs when the body or a specific tissue lacks an adequate amount of oxygen. This can be caused by reduced oxygen levels in the environment, impaired lung function, cardiovascular problems, or a reduction in blood oxygen-carrying capacity. Hypoxia is associated with several biological processes, including metabolic adaption, pathogenic microbe infections, acute and chronic illnesses, cancers, and other stress reactions. Hypoxia can manifest in several forms, including hypoxic hypoxia (due to low arterial oxygen tension), anemic hypoxia (caused by reduced hemoglobin or red blood cells), stagnant hypoxia (resulting from impaired circulation), and histotoxic hypoxia (stemming from cellular metabolic dysfunction).
Hypoxia-inducible factors (HIFs) are major regulators of downstream gene expression in response to hypoxic stress. Reduced oxygen levels in hypoxic conditions inhibit prolyl hydroxylase domain enzymes, leading to degradation avoidance and maintaining the stabilization and accumulation of HIF. Then HIFs translocate into the nucleus and initiate the transcription of genes involved in adapting to low oxygen levels. HIF signaling is tightly regulated by additional factors. Under hypoxic conditions, a high level of reactive oxygen species (ROS) generated by mitochondrial dysfunction improves HIF stability. IL-6 increases HIF-α expression by stimulating the downstream JAK-STAT3 signaling pathway. HIF-1α expression is also induced via the ERK pathway. Furthermore, ER stress can activate HIF-1α through the unfolded protein response. Additionally, HIF-1α can be influenced by various other pathways, including Wnt/β-catenin, Notch, FAT1-ROS, NF-κB, and mTOR.
Fig.1 HIF signal crosstalk with multiple pathways.1,2
In metabolic diseases like obesity, diabetes, and hypoglycemia, hypoxia triggers the activation of HIFs, primarily HIF-1α and HIF-2α, leading to inflammation within adipose tissue as well as the dysregulation of glucose metabolism, angiogenesis, and adipogenesis. Additionally, AMPK senses cellular energy status and interacts with HIFs to modulate metabolic responses to hypoxia. Other regulators, such as mTOR and sirtuins, also influence hypoxia signaling pathways in metabolic diseases.
In infectious diseases, hypoxia signaling influences host-pathogen interactions and immune responses. Pathogens such as Mycobacterium tuberculosis exploit HIF-1α to adapt to low-oxygen environments within host tissues, promoting their survival and persistence. Additionally, NF-κB, a pivotal regulator of inflammation, interacts with HIFs to modulate the immune and inflammatory responses under hypoxic conditions. Furthermore, other molecules such as ACE2, NRP1, and ROS intricately contribute to the regulation of hypoxia signaling in the context of infectious diseases.
In tumor diseases, hypoxia is a key driver of tumor growth, metastasis, and angiogenesis. HIF-1α regulates adaptive responses to hypoxia by controlling the gene expression in angiogenesis, glycolysis, and cell survival. AMPK and mTOR signaling pathways play crucial roles in sensing and integrating cellular energy status and oxygen availability, influencing HIF activity. Tumor suppressor p53 also interacts with HIFs to regulate cellular responses to hypoxia. Tumor-associated macrophages may promote cell migration and invasion by upregulating HIF-1α and Sema4D. Moreover, other regulators such as VEGF, PDGF, and TGF-β contribute to the complex regulatory network, impacting tumor angiogenesis, metastasis, and treatment response in neoplastic diseases.
Fig.2 Summarized participation of HIF-1α in tumorigenesis.1,3
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