Special Issue "Hypoxia-Inducible Factors: Regulation and Therapeutic Potential"

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 April 2021).

Special Issue Editor

Prof. Dr. Kiichi Hirota
E-Mail Website
Guest Editor
Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
Interests: hypoxia biology; cancer; metabolism; RNA-Seq; anesthesiology; bioinfomatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Molecular oxygen acts as a final electron transfer molecule in oxidative phosphorylation in mitochondria, is deeply involved in oxygen and energy metabolism, and plays a role as a factor in the regulation of iron metabolism, angiogenesis, and vascular tone.

In the late 1980s, a team led by Dr. Gregg L. Semenza in Johns Hopkins University in Baltimore, USA, decided to search for an intracellular factor involved in hypoxia-induced expression of erythropoietin and isolated the cDNA of a transcription factor in 1995. This transcription factor was designated hypoxia-inducible factor 1 (HIF-1). A closely related gene, HIF2A or EPAS1, was identified and cloned in 1997, followed by HIF3A in 1998. A series of genes, such as those coding for various glycolytic enzymes, glucose transport protein, vascular endothelial growth factor, hematopoietic factor erythropoietin, are regulated by HIFs at the transcriptional level. Thus, HIFs play a role beyond the activation of "hypoxia-inducible" genes. We could say that the term “HIF” also stands for "Highly Involved Factor".

We invite research and review papers in various areas of oxygen biology research that focus on, but not exclusively, the fundamental understanding of HIFs signaling pathways and related gene expression profiling, epigenetic regulation, diagnostic, prognostic, and pharmacogenomic biomarkers, molecular targets driving the regulation of human physiology and pathophysiology, clinical trials with new agents, and validation in animal models.

We hope that this Special Issue will reflect our exciting era with respect to the research on HIFs and its applications in medicine and health science.

Prof. Kiichi Hirota
Guest Editor

Manuscript Submission Information

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Keywords

  • hypoxia
  • oxygen biology
  • hypoxia-inducible factor
  • oxygenase
  • hydroxylase
  • angiogenesis
  • metabolism
  • cancer
  • erythropoiesis
  • apoptosis
  • iron metabolism
  • mitochondria
  • genomics
  • proteomics
  • bioinformatics
  • metagenome

Published Papers (10 papers)

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Editorial

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Editorial
Special Issue: Hypoxia-Inducible Factors: Regulation and Therapeutic Potential
Biomedicines 2021, 9(12), 1768; https://doi.org/10.3390/biomedicines9121768 (registering DOI) - 25 Nov 2021
Viewed by 112
Abstract
Oxygen (O2) is an essential molecule [1] in the production of adenosine triphosphate (ATP) in cells, and a lack of energy due to O2 deficiency makes the maintenance of biological functions and human life improbable. [...] Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)

Research

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Article
Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes
Biomedicines 2021, 9(5), 582; https://doi.org/10.3390/biomedicines9050582 - 20 May 2021
Viewed by 2914
Abstract
Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus [...] Read more.
Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Article
Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia
Biomedicines 2020, 8(11), 470; https://doi.org/10.3390/biomedicines8110470 - 03 Nov 2020
Cited by 1 | Viewed by 834
Abstract
Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the [...] Read more.
Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Article
Effect of Hypoxia Preconditioned Secretomes on Lymphangiogenic and Angiogenic Sprouting: An in Vitro Analysis
Biomedicines 2020, 8(9), 365; https://doi.org/10.3390/biomedicines8090365 - 20 Sep 2020
Cited by 2 | Viewed by 881
Abstract
Hypoxia Preconditioned Plasma (HPP) and Serum (HPS) are two blood-derived autologous growth factor compositions that are being clinically employed as tools for promoting tissue regeneration, and have been extensively examined for their angiogenic activity. As yet, their ability to stimulate/support lymphangiogenesis remains unknown, [...] Read more.
Hypoxia Preconditioned Plasma (HPP) and Serum (HPS) are two blood-derived autologous growth factor compositions that are being clinically employed as tools for promoting tissue regeneration, and have been extensively examined for their angiogenic activity. As yet, their ability to stimulate/support lymphangiogenesis remains unknown, although this is an important but often-neglected process in wound healing and tissue repair. Here we set out to characterize the potential of hypoxia preconditioned secretomes as promoters of angiogenic and lymphangiogenic sprouting in vitro. We first analysed HPP/HPS in terms of pro- (VEGF-C) and anti- (TSP-1, PF-4) angiogenic/lymphangiogenic growth factor concentration, before testing their ability to stimulate microvessel sprouting in the mouse aortic ring assay and lymphatic sprouting in the thoracic duct ring assay. The origin of lymphatic structures was validated with lymph-specific immunohistochemical staining (Anti-LYVE-1) and lymphatic vessel-associated protein (polydom) quantification in culture supernatants. HPP/HPS induced greater angiogenic and lymphatic sprouting compared to non-hypoxia preconditioned samples (normal plasma/serum), a response that was compatible with their higher VEGF-C concentration. These findings demonstrate that hypoxia preconditioned blood-derived secretomes have the ability to not only support sprouting angiogenesis, but also lymphangiogenesis, which underlines their multimodal regenerative potential. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Article
Use of Oral Anticoagulation and Diabetes Do Not Inhibit the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes
Biomedicines 2020, 8(8), 283; https://doi.org/10.3390/biomedicines8080283 - 11 Aug 2020
Cited by 2 | Viewed by 925
Abstract
Patients suffering from tissue ischemia, who would greatly benefit from angiogenesis-promoting therapies such as hypoxia preconditioned blood-derived secretomes commonly receive oral anticoagulation (OA) and/or have diabetes mellitus (DM). In this study, we investigated the effect of OA administration on the in vitro angiogenic [...] Read more.
Patients suffering from tissue ischemia, who would greatly benefit from angiogenesis-promoting therapies such as hypoxia preconditioned blood-derived secretomes commonly receive oral anticoagulation (OA) and/or have diabetes mellitus (DM). In this study, we investigated the effect of OA administration on the in vitro angiogenic potential of hypoxia preconditioned plasma (HPP) and serum (HPS), prepared from nondiabetic/diabetic subjects who did not receive OA (n = 5) or were treated with acetylsalicylic acid (ASA, n = 8), ASA + clopidogrel (n = 10), or nonvitamin K antagonist oral anticoagulants (n = 7) for longer than six months. The effect of DM was differentially assessed by comparing HPP/HPS obtained from nondiabetic (n = 8) and diabetic (n = 16) subjects who had not received OA in the past six months. The concentration of key proangiogenic (vascular endothelial growth factor or VEGF) and antiangiogenic (thrombospondin-1 or TSP-1 and platelet factor-4 or PF-4) protein factors in HPP/HPS was analyzed via ELISA, while their ability to induce microvessel formations was examined in endothelial cell cultures. We found that OA use significantly reduced VEGF levels in HPP, but not HPS, compared to non-OA controls. While HPP and HPS TSP-1 levels remained largely unchanged as a result of OA usage, HPS PF-4 levels were significantly reduced in samples obtained from OA-treated subjects. Neither OA administration nor DM appeared to significantly reduce the ability of HPP or HPS to induce microvessel formations in vitro. These findings indicate that OA administration does not limit the angiogenic potential of hypoxia preconditioned blood-derived secretomes, and therefore, it does not prohibit the application of these therapies for supporting tissue vascularization and wound healing in healthy or diabetic subjects. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Article
Comparative Evaluation of the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes and Platelet-Rich Plasma: An In Vitro Analysis
Biomedicines 2020, 8(1), 16; https://doi.org/10.3390/biomedicines8010016 - 16 Jan 2020
Cited by 3 | Viewed by 1776
Abstract
Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum [...] Read more.
Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum (HPS). The concentration of key pro-angiogenic (VEGF) and anti-angiogenic (TSP-1, PF-4) protein factors in these secretomes was analyzed via ELISA, while their ability to induce microvessel formation and sprouting was examined in endothelial cell and aortic ring cultures, respectively. We found higher concentrations of VEGF in PRP and HPP/HPS compared to normal plasma and serum. This correlated with improved induction of microvessel formation by PRP and HPP/HPS. HPP had a significantly lower TSP-1 and PF-4 concentration than PRP and HPS. PRP and HPP/HPS appeared to induce similar levels of microvessel sprouting; however, the length of these sprouts was greater in HPP/HPS than in PRP cultures. A bell-shaped angiogenic response profile was observed with increasing HPP/HPS dilutions, with peak values significantly exceeding the PRP response. Our findings demonstrate that optimization of peripheral blood cell-derived angiogenic factor signalling through hypoxic preconditioning offers an improved alternative to simple platelet concentration and release of growth factors pre-stored in platelets. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Article
Meta-Analysis of Hypoxic Transcriptomes from Public Databases
Biomedicines 2020, 8(1), 10; https://doi.org/10.3390/biomedicines8010010 - 09 Jan 2020
Cited by 8 | Viewed by 2715
Abstract
Hypoxia is the insufficiency of oxygen in the cell, and hypoxia-inducible factors (HIFs) are central regulators of oxygen homeostasis. In order to obtain functional insights into the hypoxic response in a data-driven way, we attempted a meta-analysis of the RNA-seq data from the [...] Read more.
Hypoxia is the insufficiency of oxygen in the cell, and hypoxia-inducible factors (HIFs) are central regulators of oxygen homeostasis. In order to obtain functional insights into the hypoxic response in a data-driven way, we attempted a meta-analysis of the RNA-seq data from the hypoxic transcriptomes archived in public databases. In view of methodological variability of archived data in the databases, we first manually curated RNA-seq data from appropriate pairs of transcriptomes before and after hypoxic stress. These included 128 human and 52 murine transcriptome pairs. We classified the results of experiments for each gene into three categories: upregulated, downregulated, and unchanged. Hypoxic transcriptomes were then compared between humans and mice to identify common hypoxia-responsive genes. In addition, meta-analyzed hypoxic transcriptome data were integrated with public ChIP-seq data on the known human HIFs, HIF-1 and HIF-2, to provide insights into hypoxia-responsive pathways involving direct transcription factor binding. This study provides a useful resource for hypoxia research. It also demonstrates the potential of a meta-analysis approach to public gene expression databases for selecting candidate genes from gene expression profiles generated under various experimental conditions. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Review

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Review
HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review
Biomedicines 2021, 9(5), 468; https://doi.org/10.3390/biomedicines9050468 - 24 Apr 2021
Cited by 6 | Viewed by 1415
Abstract
Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at [...] Read more.
Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Review
Hypoxia/HIF Modulates Immune Responses
Biomedicines 2021, 9(3), 260; https://doi.org/10.3390/biomedicines9030260 - 05 Mar 2021
Cited by 4 | Viewed by 995
Abstract
Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological [...] Read more.
Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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Review
Basic Biology of Hypoxic Responses Mediated by the Transcription Factor HIFs and Its Implication for Medicine
Biomedicines 2020, 8(2), 32; https://doi.org/10.3390/biomedicines8020032 - 13 Feb 2020
Cited by 13 | Viewed by 2026
Abstract
Oxygen (O2) is essential for human life. Molecular oxygen is vital for the production of adenosine triphosphate (ATP) in human cells. O2 deficiency leads to a reduction in the energy levels that are required to maintain biological functions. O2 [...] Read more.
Oxygen (O2) is essential for human life. Molecular oxygen is vital for the production of adenosine triphosphate (ATP) in human cells. O2 deficiency leads to a reduction in the energy levels that are required to maintain biological functions. O2 acts as the final acceptor of electrons during oxidative phosphorylation, a series of ATP synthesis reactions that occur in conjunction with the electron transport system in mitochondria. Persistent O2 deficiency may cause death due to malfunctioning biological processes. The above account summarizes the classic view of oxygen. However, this classic view has been reviewed over the last two decades. Although O2 is essential for life, higher organisms such as mammals are unable to biosynthesize molecular O2 in the body. Because the multiple organs of higher organisms are constantly exposed to the risk of “O2 deficiency,” living organisms have evolved elaborate strategies to respond to hypoxia. In this review, I will describe the system that governs oxygen homeostasis in the living body from the point-of-view of the transcription factor hypoxia-inducible factor (HIF). Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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