Role Of Hypoxia-inducible Factor Research Articles

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer.

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

From the Editor’s Desk...

From the Editor’s Desk...

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target.

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

Hypoxia signaling in renal pericytes—is it safe to activate?

While excitement has grown for the use of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors for treating renal anemia, multiple preclinical studies have shown the complex and cell-type-dependent roles of HIFs in kidney disease pathogenesis, including renal fibrosis. Pan etal. now clearly show that activating the HIF signaling in the Gli1-lineage myofibroblasts restores erythropoietin production while not adversely affecting matrix production, mitigating the concerns of exacerbated fibrosis by HIF prolyl hydroxylase inhibitors.

Expression of hypoxia-inducible factor-1 in mice infected with Toxoplasma gondii during pregnancy

To investigate the expression and possible role of hypoxia-inducible factor-1 (HIF-1) at the maternal-fetal interface following Toxoplasma gondii infection during early pregnancy. Twenty pregnant C57BL/6 mice, each weighing 16 to 20 g, were randomly divided into 4 groups, including the 12-d control group, 12-d infection group, 18-d control group and 18-d infection group. Mice in the 12-d and 18-d infection groups were injected intraperitoneally with 150 tachyzoites of the T. gondii PRU strain on day 6 of pregnancy, while mice in the 12-d control and 18-d control groups were injected with the same volume of phosphate buffered saline (PBS). Mice in the control and infection groups were sacrificed on days 12 and 18 of pregnancy, and the placental and uterine specimens of the pregnant mice in each group were sampled for pathological examinations. The mRNA expression of HIF-1α, HIF-1β and vascular endothelial growth factor (VEGF) was quantified using quantitative fluorescent real-time PCR (qPCR) assay in the placental and uterine specimens, and the correlation between HIF-1α and VEGF mRNA expression was examined. In addition, and the HIF-1α expression was detected using immunohistochemical staining in the placental and uterine specimens of pregnant mice. Compared with the 12-d and 18-d control groups, adverse pregnant outcomes were observed in mice in 12-d and 18-d infection groups, such as teratism and placental dysplasia. HE staining showed swelling and blood stasis of cells, sinusoid reduction and inflammatory cell infiltration in the labyrinth area of the placenta specimens of mice in 12-d and 18-d infection groups relative to 12-d and 18-d control groups, and columnar epithelial cell injury and inflammatory cell infiltration were seen in the mouse uterine specimens in both infection groups. qPCR assay detected significantly higher HIF-1α (F = 132.6, P < 0.05) and HIF-1β mRNA expression (F = 286.9, P < 0.05) in the placental specimens and lower HIF-1α (F = 111.5, P < 0.05) and HIF-1β mRNA expression (F = 55.2, P < 0.05) in the uterine specimens in the 12-d infection group than in the 12-day control group, and significantly lower HIF-1α and HIF-1β mRNA expression was detected in the placental and uterine specimens in the 18-d infection group than in the 18-day control group (F = 215.8, 418.9, 156.8 and 200.1; all P values < 0.05). Significantly lower VEGF-A (F = 426.2, P < 0.05), VEGF-B (F = 104.6, P < 0.05) and VEGF-C mRNA expression (F = 566.9, P < 0.05) in the placental specimens and higher VEGF-A (F = 426.2, P < 0.05), VEGF-B (F = 104.6, P < 0.05) and VEGF-C mRNA expression (F = 566.9, P < 0.05) in the uterine specimens were detected in the 12-d infection group than in the 12-d control group, and higher VEGF-A, VEGF-B and VEGF-C mRNA expression was found in the placental and uterine specimens in the 18-d infection group than in the 18-d control group (F = 521.9, 100.6, 275.9, 224.6, 108.2 and 333.4; all P values < 0.05). Immunohistochemical staining showed strongly and mildly positive HIF-1α expression in the mouse placental labyrinth area in the 12-d and 18-d infection groups relative to 12-d and 18-d control groups, while no HIF-1α expression was detected in mouse uterine specimens. HIF-1α expression appears a tendency towards a rise in the second trimester and a reduction in the third trimester in mice following T. gondii infection during early pregnancy, which is contrary to the changing tendency of VEGF-A, VEGF-B, and VEGF-C expression. It is hypothesized that HIF-1α inhibits placental angiogenesis in mice during pregnancy through suppressing VEGF expression, resulting in adverse pregnant outcomes.

Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target. Therefore, we examine the aberrant HIF-1 stabilization in BMs from MDS patients and controls (CTRLs). Using a nitroimidazole–indocyanine conjugate, we show that HIF-1 aberrant expression and transcription activity is oxygen independent, establishing the phenomenon of pseudohypoxia in MDS BM. Next, we examine mitochondrial quality and quantity along with levels of autophagy in the differentiating myeloid lineage isolated from fresh BM MDS and CTRL aspirates given that both phenomena are HIF-1 dependent. We show that the mitophagy of abnormal mitochondria and autophagic death are prominently featured in the MDS myeloid lineage, their severity increasing with intra-BM blast counts. Finally, we use in vitro cultured CD34+ HSCs isolated from fresh human BM aspirates to manipulate HIF-1 expression and examine its potential as a therapeutic target. We find that despite being cultured under 21% FiO2, HIF-1 remained aberrantly stable in all MDS cultures. Inhibition of the HIF-1α subunit had a variable beneficial effect in all <5%-intra-BM blasts-MDS, while it had no effect in CTRLs or in ≥5%-intra-BM blasts-MDS that uniformly died within 3 days of culture. We conclude that HIF-1 and pseudohypoxia are prominently featured in MDS pathobiology, and their manipulation has some potential in the therapeutics of benign MDS.

Abstract IA-017: Chromatin and gene transcription in hypoxia

Abstract Oxygen is essential for the life of most multicellular organism and changes in oxygen availability have implications in physiological and pathophysiological conditions. In response to hypoxia (low oxygen availability) transcriptional changes are induced. The transcriptional response to hypoxia is mediated primarily by the Hypoxia Inducible Factor (HIF) family of transcription factors. HIFs are activated in hypoxia via inhibition of prolyl hydroxylases (PHDs), a group of molecular dioxygenases, which require oxygen for their activity. Whilst the role of HIFs in the transcriptional response to hypoxia is well characterized, little is known with regards to chromatin structure in low oxygen stress and how this coordinates the transcriptional response. It was recently shown that chromatin is sensitive to oxygen levels, with hypoxia altering histone methylation at hypoxia responsive genes via inhibition of specific JmjC histone demethylases. To further investigate chromatin structure and its role in hypoxia induced gene transcription, we have performed ATAC-seq and RNA-seq in human cancer cell lines in acute and prolonged hypoxia. We find that acute hypoxia leads to increased promoter accessibility at a subset of hypoxia inducible genes, and this mostly precedes changes in mRNA expression, with further changes in chromatin structure after prolonged hypoxia. In addition, ChIP-seq data on histone methylation marks (H3K4me and H3K36me3), revealed similar earlier patterns of genomic distribution. Furthermore, we dissected the impact of HIF in the observed changes using a chemical probe and specific HIF1beta depletion analysis of ATAC-seq. This work gives insights into the role of chromatin dynamics in regulating the transcriptional response to hypoxia and elucidating the mechanisms behind these changes may lead to targeted therapies for hypoxia driven diseases. Citation Format: Michael Batie, Julianty Frost, Sonia Rocha. Chromatin and gene transcription in hypoxia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-017.

Hypoxia and viral infectious diseases.

Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.

Hypoxia/HIF Modulates Immune Responses.

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.

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia.

Simple SummaryHypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that such dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation.Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

Hypoxia-inducible Factors—Their Regulation and Function in Neural Tissue

Hypoxia-inducible factors (HIF) are key transcription factors that alter gene expression in hypoxia, and play a central role in ensuring an adaptive response to low oxygen levels in the brain. This review provides information on the functional role of HIF in adaptive tissue responses, specifically in response to metabolic shifts, in angiogenesis, apoptosis and others, which plays an important role in cell survival under hypoxic conditions. We describe the molecular structure of the main HIF subunits, changes in their expression and decay at normal oxygen levels, as well as in acute and chronic hypoxia, and the factors regulating these changes. Special attention is paid to the role of microRNAs in regulating HIF changes, as well as the interaction of HIF subunits with mitochondrial factors. The role of HIF in neuroprotection and neuroglial adaptive changes is described in detail. The importance of further study of HIF’s physiological role is noted, to obtain new information about the pathogenesis of hypoxic brain injury, including its early stages, which determines the risk of later neurological disease.

HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation.

The ovarian follicle provides the oocyte with the ideal environment for growth and development in preparation for ovulation and fertilisation. The follicle undergoes many structural changes as it grows, including changes in vasculature, cell proliferation and differentiation and the formation of a fluid-filled antrum. These changes collectively create a low oxygen environment within the follicle. Thus, the oocyte itself develops in a potentially hypoxic environment. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. The understanding of HIF pathways is growing across all fields of biology, and its role in ovarian development is steadily gaining clarity. One of the genes upregulated by HIF is a vascular endothelial growth factor, the main inducer of angiogenesis which is required for follicle development and corpus formation. Ovulation is also intrinsically linked to HIF activity through the ovulatory luteinising hormone surge increasing HIF expression. The role for HIF in oocyte maturation is less understood, as efforts to replicate the low oxygen environment of the in vivo follicle are not achievable by culturing in low oxygen alone. There is potential for other factors present in vivo, but lost in vitro, to be involved in oxygen regulation. One factor of interest is haemoglobin, the oxygen-binding protein, which brings the exciting possibility of sensitive oxygen regulation, consequently affecting HIF-regulated gene expression. A thorough understanding of oxygen regulation within the follicle would provide vital applications for the field of assisted reproductive technologies, in particular in vitro oocyte maturation.

Hypoxic preconditioning — A nonpharmacological approach in COVID-19 prevention

Hypoxia is defined by low oxygen concentration in organs, tissues, and cells. Maintaining oxygen homeostasis represents the essential cellular metabolic process for the structural integrity of tissues in different pathological conditions, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Considering the role of hypoxia-inducible factor-1 as the regulator of cellular response to hypoxia and its involvement in angiogenesis, erythropoiesis, glucose metabolism, inflammation, we propose hypoxic preconditioning (HPC) as a novel prevention therapeutic approach on healthy contacts of patients with coronavirus disease-2019 (COVID-19). To date, several studies revealed the beneficial effects of HPC in ischemia, kidney failure, and in pulmonary function recovery of patients who underwent lung surgery. HPC increases the expression of factors that promote cell survival and angiogenesis, induces an anti-inflammatory outcome, triggers coordinated hypoxia responses that promote erythropoiesis, and mobilizes the circulating progenitor cells. Furthermore, the mesenchymal stem cells (MSC) exposed to HPC show improvement of their regenerative capacities and increases the effectiveness of stem cell therapy in different pathologies, including COVID-19. In conclusion, HPC should be considered as an approach with beneficial outcomes and without significant side effects when the organism is severely exposed to the same stressor. HPC appears as a trigger to mechanisms that improve and maintain tissue oxygenation and repair, a main goal in different pathologies, including COVID-19 or other respiratory conditions.

Role of hypoxia inducible factor-1 in cancer stem cells (Review).

Cancer stem cells (CSCs) have been found to play a decisive role in cancer recurrence, metastasis, and chemo-, radio- and immuno-resistance. Understanding the mechanism of CSC self-renewal and proliferation may help overcome the limitations of clinical treatment. The microenvironment of tumor growth consists of a lack of oxygen, and hypoxia has been confirmed to induce cancer cell invasion, metastasis and epithelial-mesenchymal transition, and is usually associated with poor prognosis and low survival rates. Hypoxia inducible factor-1 (HIF-1) can be stably expressed under hypoxia and act as an important molecule to regulate the development of CSCs, but the specific mechanism remains unclear. The present review attempted to explain the role of HIF-1 in the generation and maintenance of CSCs from the perspective of epigenetics, metabolic reprogramming, tumor immunity, CSC markers, non-coding RNA and signaling pathways associated with HIF-1, in order to provide novel targets with HIF-1 as the core for clinical treatment, and extend the life of patients.

Role of Hypoxia-Inducible Factors in Regulating Right Ventricular Function and Remodeling during Chronic Hypoxia–induced Pulmonary Hypertension

Pulmonary hypertension (PH) and right ventricular (RV) hypertrophy frequently develop in patients with hypoxic lung disease. Chronic alveolar hypoxia (CH) promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling by acting on lung cells, resulting in the development of PH. RV hypertrophy develops in response to PH, but coronary arterial hypoxemia in CH may influence that response by activating HIF-1α (hypoxia-inducible factor 1α) and/or HIF-2α in cardiomyocytes. Indeed, other studies show that the attenuation of PH in CH fails to prevent RV remodeling, suggesting that PH-independent factors regulate RV hypertrophy. Therefore, we examined the role of HIFs in RV remodeling in CH-induced PH. We deleted HIF-1α and/or HIF-2α in hearts of adult mice that were then housed under normoxia or CH (10% O2) for 4 weeks. RNA-sequencing analysis of the RV revealed that HIF-1α and HIF-2α regulate the transcription of largely distinct gene sets during CH. RV systolic pressure increased, and RV hypertrophy developed in CH. The deletion of HIF-1α in smooth muscle attenuated the CH-induced increases in RV systolic pressure but did not decrease hypertrophy. The deletion of HIF-1α in cardiomyocytes amplified RV remodeling; this was abrogated by the simultaneous loss of HIF-2α. CH decreased stroke volume and cardiac output in wild-type but not in HIF-1α-deficient hearts, suggesting that CH may cause cardiac dysfunction via HIF-dependent signaling. Collectively, these data reveal that HIF-1 and HIF-2 act together in RV cardiomyocytes to orchestrate RV remodeling in CH, with HIF-1 playing a protective role rather than driving hypertrophy.

Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia.

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1-/- mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic β-cell dysfunction.

HIF-1\u03b1 expression in liver metastasis but not primary colorectal cancer is associated with prognosis of patients with colorectal liver metastasis

BackgroundThe role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear. The aim of this study was to investigate HIF-1α expression and its association with prognosis in patients with CRLM with a focus on hepatic stellate cells (HSCs).MethodsColon cancer cells were cultured in HSC-conditioned medium (CM), and HIF-1α expression and cell migration were analyzed. Seventy-five patients with CRLM who underwent an initial curative hepatectomy were enrolled. We examined HIF-1α expressions and patient prognosis between primary CRCs and the matched liver metastatic specimens.ResultsActivated HSCs induced HIF-1α mRNA and protein expression in colon cancer cells (p < 0.01) and promoted cell migration (p < 0.01). The positive rates of HIF-1α expression in primary CRCs and liver metastases were 68.0 and 72.0%, respectively. There were no differences in overall (OS) and disease-free survival (DFS) of HIF-1α expression in primary CRC. However, HIF-1α expression in liver metastasis correlated to poor prognosis in both OS and DFS. Furthermore, patients with HIF-1α positive expression in liver metastasis had poor prognosis.ConclusionHIF-1α expression in liver metastasis determines poor prognosis of CRLM patients. HSCs might play a key role in aggressive phenotypes of tumor cells.

Neuroprotection of hypoxic/ischemic preconditioning in neonatal brain with hypoxic-ischemic injury.

The neonatal brain is susceptible to hypoxic-ischemic injury due to its developmental characteristics. Hypoxia-ischemia means a decreased perfusion of oxygen and glucose, which can lead to severe encephalopathy. Although early initiation of therapeutic hypothermia was reported to provide neuroprotection for infants after HI, hypothermia administered alone after the acute insult cannot reverse the severe damage that already has occurred or improve the prognosis of severe hypoxic-ischemic encephalopathy. Therefore, exploring new protective mechanisms for treating hypoxic-ischemic brain damage are imperative. Until now, many studies reported the neuroprotective mechanisms of hypoxic/ischemic preconditioning in protecting the hypoxic-ischemic newborn brains. After hypoxia and ischemia, hypoxia-inducible factor signaling pathway is involved in the transcriptional regulation of many genes and is also play a number of different roles in protecting brains during hypoxic/ischemic preconditioning. Hypoxic/ischemic preconditioning could protect neonatal brain by several mechanisms, including vascular regulation, anti-apoptosis, anti-oxidation, suppression of excitotoxicity, immune regulation, hormone levels regulation, and promote cell proliferation. This review focused on the protective mechanisms underlying hypoxic/ischemic preconditioning for neonatal brain after hypoxia-ischemia and emphasized on the important roles of hypoxia inducible factor 1 signaling pathway.

Hypoxia-inducible factors and obstructive sleep apnea.

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.

Barrier integrity and chronic inflammation mediated by HIF-1 impact on intestinal tumorigenesis

Colorectal cancer ranks among the top three most frequent malignancies in the world. While overall incidence and mortality of colorectal cancer has substantially decreased in recent years, tumor subtypes with poor response rates to standard antiproliferative therapies remain particularly challenging. Hypoxia in the microenvironment of solid tumors is associated with malignant progression, e.g. local invasion, systemic spread and therapy resistance. A detailed molecular understanding of hypoxia's role for the pathobiology of colorectal cancer is a prerequisite to design and evaluate the consequences of interference with hypoxic signaling for the progression of this cancer type. Here, we summarize the current knowledge about the role of hypoxia-inducible factor 1, an essential molecular mediator of the hypoxic response, for colorectal cancer pathogenesis. Special attention is given to intestinal microbiota, gut barrier integrity and chronic inflammation as these are of pivotal importance for intestinal tumorigenesis and noticeably associated with hypoxic signaling.