scholarly journals Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2

2012 ◽  
Vol 92 (3) ◽  
pp. 967-1003 ◽  
Author(s):  
Nanduri R. Prabhakar ◽  
Gregg L. Semenza
Keyword(s):  
Transcriptional Activation ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Physiological Adaptations ◽  
Prolyl Hydroxylation ◽  
Insight Into ◽  
Subsequent Identification

Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O2-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O2availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O2sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.

Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1

Physiology ◽  
2009 ◽  
Vol 24 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Systemic Hypertension ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding

Metazoan organisms are dependent on a continuous supply of O2 for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca2+ signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.

scholarly journals HIF-1: the knowns and unknowns of hypoxia sensing.

2004 ◽  
Vol 51 (3) ◽  
pp. 563-585 ◽  
Author(s):  
Anna Zagórska ◽  
Józef Dulak
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Oxygen Homeostasis ◽  
Wide Range ◽  
Systemic Oxygen ◽  
Prolyl Hydroxylation ◽  
Energy Deprivation ◽  
Direct Inhibitors

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that functions as a master regulator of cellular and systemic oxygen homeostasis. It consists of two constitutively produced subunits: HIF-1alpha and HIF-1beta. Under normoxic conditions HIF-1alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the alpha subunit. Additionally, hydroxylation of an asparaginyl residue blocks the transcriptional activity of HIF-1 due to inhibition of its interaction with co-activators. In contrast, under hypoxic conditions, abolition of prolyl hydroxylation results in HIF-1alpha stabilization, whereas the lack of asparaginyl hydroxylation allows the transcriptional activity. Additionally, the transcriptional activity may be modulated by phosphorylation or redox modification of HIF-1. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, various growth factors, or direct inhibitors of prolyl and asparaginyl hydroxylases. Therefore, it seems to be a crucial transcription factor elicited by a wide range of stresses such as impaired oxygenation, inflammation, energy deprivation, or intensive proliferation. However, the mechanisms of normoxic activation, as well as of oxygen sensing, are not yet fully known. Further understanding of the processes that control HIF-1 activity will be crucial for the development of new diagnostic and therapeutic strategies.

scholarly journals Stage-dependent effects of intermittent hypoxia influence the outcome of hippocampal adult neurogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maggie A. Khuu ◽  
Thara Nallamothu ◽  
Carolina I. Castro-Rivera ◽  
Alejandra Arias-Cavieres ◽  
Caroline C. Szujewski ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Adult Neurogenesis ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Memory Deficits ◽  
Brain Health ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Dependent Cell ◽  
Adult Born Neurons

AbstractOver one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer’s disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.

scholarly journals The Hypoxia-Inducible Factor 1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia

2009 ◽  
Vol 29 (21) ◽  
pp. 5828-5842 ◽  
Author(s):  
Lluis Martorell ◽  
Maurizio Gentile ◽  
Jordi Rius ◽  
Cristina Rodríguez ◽  
Javier Crespo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Orphan Receptor ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Hypoxia Inducible Factor 1 ◽  
Apoptosis Protein

ABSTRACT Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1α protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca2+ was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2015-2019 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Blood Cells ◽  
Tissue Oxygenation ◽  
Hypoxia Inducible Factor ◽  
Α Subunit ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding ◽  
Asparaginyl Hydroxylase

Abstract Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

scholarly journals Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E8 ◽  
Author(s):  
Matthew Womeldorff ◽  
David Gillespie ◽  
Randy L. Jensen
Keyword(s):  
Cellular Response ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Poor Patient ◽  
Growth Development ◽  
The Relationship ◽  
Insight Into ◽  
Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

scholarly journals Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

Oncotarget ◽  
2017 ◽  
Vol 8 (37) ◽  
pp. 61592-61603 ◽  
Author(s):  
Dae Wui Yoon ◽  
Daeho So ◽  
Sra Min ◽  
Jiyoung Kim ◽  
Mingyu Lee ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1

scholarly journals Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

2002 ◽  
Vol 22 (9) ◽  
pp. 2984-2992 ◽  
Author(s):  
Nianli Sang ◽  
Jie Fang ◽  
Vickram Srinivas ◽  
Irene Leshchinsky ◽  
Jaime Caro
Keyword(s):  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Physical Interaction ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Transactivation Activity ◽  
Oxygen Homeostasis ◽  
Stimulation Of

ABSTRACT Hypoxia-inducible factor 1 complex (HIF-1) plays a pivotal role in oxygen homeostasis and adaptation to hypoxia. Its function is controlled by both the protein stability and the transactivation activity of its alpha subunit, HIF-1α. Hydroxylation of at least two prolyl residues in the oxygen-dependent degradation domain of HIF-1α regulates its interaction with the von Hippel-Lindau protein (VHL) that targets HIF-1α for ubiquitination and proteasomal degradation. Several prolyl hydroxylases have been found to specifically hydroxylate HIF-1α. In this report, we investigated possible roles of VHL and hydroxylases in the regulation of the transactivation activity of the C-terminal activating domain (CAD) of HIF-1α. We demonstrate that regulation of the transactivation activity of HIF-1α CAD also involves hydroxylase activity but does not require functional VHL. In addition, stimulation of the CAD activity by a hydoxylase inhibitor, hypoxia, and desferrioxamine was severely blocked by the adenoviral oncoprotein E1A but not by an E1A mutant defective in targeting p300/CBP. We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1α CAD and p300/CBP in vivo. Taken together, our data provide evidence that hypoxia-regulated stabilization and transcriptional stimulation of HIF-1α function are regulated through partially overlapping but distinguishable pathways.

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