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Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair.
Evans, CE
Cells. 2022;(2)
Abstract
Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC-LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC-LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.
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2.
DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance.
D'Anna, F, Van Dyck, L, Xiong, J, Zhao, H, Berrens, RV, Qian, J, Bieniasz-Krzywiec, P, Chandra, V, Schoonjans, L, Matthews, J, et al
Genome biology. 2020;(1):182
Abstract
BACKGROUND Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia. RESULTS We report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modeling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid down by the differential expression and binding of other transcription factors under normoxia, control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumors with high immune checkpoint expression, but not in tumors with low immune checkpoint expression, where they would compromise tumor immunotolerance. In a low-immunogenic tumor model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumor growth. CONCLUSIONS Our data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.
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3.
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Patients with Renal Anemia: A Meta-Analysis of Randomized Trials.
Wen, T, Zhang, X, Wang, Z, Zhou, R
Nephron. 2020;(11):572-582
Abstract
BACKGROUND Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of treatment for renal anemia in patients with chronic kidney disease (CKD). This meta-analysis was designed to evaluate their efficacy and safety. METHOD Eight databases were searched for randomized controlled trials (RCTs). Information about efficacy and safety was extracted and combined using random-effects or fixed-effects models, depending on heterogeneity. Risk of bias was assessed using the method recommended by the Cochrane Centre. RESULTS Nineteen articles on RCTs were selected, involving 3,289 participants. We found that HIF-PHIs improved the level of hemoglobin (Hb) (weighted mean difference [WMD] 1.40; 95% CI: 0.96-1.84; p < 0.001), response rate of Hb (risk ratio [RR] 5.95; 95% CI: 3.95-8.96; p < 0.001), and total iron-binding capacity (WMD 42.94; 95% CI: 31.39-54.49; p < 0.001), while reducing the level of hepcidin (WMD -40.42; 95% CI: -50.44 to -30.39; p < 0.001), ferritin (WMD -64.60; 95% CI: -78.56 to -50.64; p < 0.001), and transferrin saturation (WMD -5.57; 95% CI: -8.53 to -2.61; p < 0.001). Meanwhile, there was no evidence of effect on serum iron (WMD 1.60; 95% CI: -3.72 to 6.93; p = 0.55), nor on the incidence of adverse events (AEs) (RR 1.06; 95% CI: 0.99-1.15; p = 0.51) or of serious adverse events (SAEs) (RR 1.14; 95% CI: 0.88-1.46; p = 0.32). CONCLUSION HIF-PHIs ameliorate renal anemia and rectify iron metabolism in the short term without increasing the incidence of AEs and SAEs.
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Uncovering the protective mechanism of Taohong Siwu decoction against diabetic retinopathy via HIF-1 signaling pathway based on network analysis and experimental validation.
Wang, L, Li, S, Wang, L, Lin, K, Du, J, Miao, W, Zhang, L
BMC complementary medicine and therapies. 2020;(1):298
Abstract
BACKGROUND Diabetic retinopathy (DR) is a common and serious microvascular complication of diabetes. Taohong Siwu decoction (THSWD), a famous traditional Chinese medicine (TCM) prescription, has been proved to have a good clinical effect on DR, whereas its molecular mechanism remains unclear. Our study aimed to uncover the core targets and signaling pathways of THSWD against DR. METHODS First, the active ingredients of THSWD were searched from Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database. Second, the targets of active ingredients were identified from ChemMapper and PharmMapper databases. Third, DR associated targets were searched from DisGeNET, DrugBank and Therapeutic Target Database (TTD). Subsequently, the common targets of active ingredients and DR were found and analyzed in STRING database. DAVID database and ClueGo plug-in software were used to carry out the gene ontology (GO) and KEGG enrichment analysis. The core signaling pathway network of "herb-ingredient-target" was constructed by the Cytoscape software. Finally, the key genes of THSWD against DR were validated by quantitative real-time PCR (qRT-PCR). RESULTS A total of 2340 targets of 61 active ingredients in THSWD were obtained. Simultaneously, a total of 263 DR-associated targets were also obtained. Then, 67 common targets were found by overlapping them, and 23 core targets were identified from protein-protein interaction (PPI) network. Response to hypoxia was found as the top GO term of biological process, and HIF-1 signaling pathway was found as the top KEGG pathway. Among the key genes in HIF-1 pathway, the mRNA expression levels of VEGFA, SERPINE1 and NOS2 were significantly down-regulated by THSWD (P < 0.05), and NOS3 and HMOX1 were significantly up-regulated (P < 0.05). CONCLUSION THSWD had a protective effect on DR via regulating HIF-1 signaling pathway and other important pathways. This study might provide a theoretical basis for the application of THSWD and the development of new drugs for the treatment of DR.
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Update on mutations in the HIF: EPO pathway and their role in erythrocytosis.
Lappin, TR, Lee, FS
Blood reviews. 2019;:100590
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Abstract
Identification of the underlying defects in congenital erythrocytosis has provided mechanistic insights into the regulation of erythropoiesis and oxygen homeostasis. The Hypoxia Inducible Factor (HIF) pathway plays a key role in this regard. In this pathway, an enzyme, Prolyl Hydroxylase Domain protein 2 (PHD2), constitutively prolyl hydroxylates HIF-2α, thereby targeting HIF-2α for degradation by the von Hippel Lindau (VHL) tumor suppressor protein. Under hypoxia, this modification is attenuated, resulting in the stabilization of HIF-2α and transcriptional activation of the erythropoietin (EPO) gene. Circulating EPO then binds to the EPO receptor (EPOR) on red cell progenitors in the bone marrow, leading to expansion of red cell mass. Loss of function mutations in PHD2 and VHL, as well as gain of function mutations in HIF-2α and EPOR, are well established causes of erythrocytosis. Here, we highlight recent developments that show that the study of this condition is still evolving. Specifically, novel mutations have been identified that either change amino acids in the zinc finger domain of PHD2 or alter splicing of the VHL gene. In addition, continued study of HIF-2α mutations has revealed a distinctive genotype-phenotype correlation. Finally, novel mutations have recently been identified in the EPO gene itself. Thus, the cascade of genes that at a molecular level leads to EPO action, namely PHD2 - > HIF2A - > VHL - > EPO - > EPOR, are all mutational targets in congenital erythrocytosis.
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[Current insights into the role of HIF-PHD axis in renal anemia].
Cao, JY, Liu, BC
Sheng li xue bao : [Acta physiologica Sinica]. 2018;(6):623-629
Abstract
Renal anemia, mainly caused by the deficiencies of erythropoietin (EPO) and iron metabolism disorder, is one of the most common complications of chronic kidney disease. Hypoxia-inducible factor (HIF) is a class of transcription factors responsible for maintaining homeostasis during oxygen deprivation. In normoxia, HIF is degraded by prolyl hydroxylase (PHD). While under hypoxic conditions, the hydroxylation activity of PHD is inhibited, and the cellular concentration of HIF is elevated, resulting in an increase in endogenous EPO production and iron absorption. Therefore, this regulating pathway, also termed as the HIF-PHD axis, has become a promising therapeutic target of treating renal anemia. Several innovative drugs acting as selective HIF-PHD inhibitors have been successfully developed in the past years, and some of them are undergoing clinical trials. In this review, we will introduce the definition and regulatory mechanism of HIF-PHD axis, as well as current insights into its physiologic and therapeutic role in renal anemia.
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Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease.
Kaplan, JM, Sharma, N, Dikdan, S
International journal of molecular sciences. 2018;(2)
Abstract
Hypoxia-inducible factor (HIF) plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD) as well as in multiple other disease states involving ischemia-reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI) in these patients. Additionally, articles reporting the clinical potential for HIF-PHIs in 'other' putative therapeutic areas, the tissue and intracellular distribution of HIF- and prolyl-hydroxylase domain (PHD) isoforms, and HIF isoforms targeted by the different PHDs, were identified. There is increasing uncertainty regarding the optimal treatment for anemia of CKD with poorer outcomes associated with treatment to higher hemoglobin targets, and the increasing use of iron and consequent risk of iron imbalance. Attainment and maintenance of more physiologic erythropoietin levels associated with HIF stabilization may improve the management of patients resistant to treatment with erythropoiesis-stimulating agents and improve outcomes at higher hemoglobin targets.
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[Is Oxygen Deficiency Always Harmful?].
Schläpfer, M
Praxis. 2018;(21):1155-1159
Abstract
Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.
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New Strategies for Anaemia Management in Chronic Kidney Disease.
Locatelli, F, Del Vecchio, L
Contributions to nephrology. 2017;:184-188
Abstract
Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality. A more cautious approach was then advised and partial anaemia correction (haemoglobin 10-12 g/dl) is now strongly suggested. The clinical concerns about ESAs and economic constraints have led to larger intravenous iron use. However, severe anaphylactic reactions, although infrequent, can occur and excessive iron use may be dangerous as well, possibly causing iron overload. Several attempts are being made to develop new drugs with theoretically better activity and safety, and/or easier manufacturing processes as compared to available ESAs. These include drugs manipulating the hypoxia-inducible transcription factor (HIF) system, which stimulates the endogenous erythropoietin (EPO) production and avoids unphysiological EPO plasma levels. Several phase I and II studies support the beneficial role of augmenting HIFs to stimulate erythropoiesis. Here we give an update on this new investigational strategy.
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Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype.
Semenza, GL
The EMBO journal. 2017;(3):252-259
Abstract
Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer.