Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α

Hagen, Thilo; Taylor, Cormac T.; Lam, Francis; Moncada, Salvador

doi:10.1126/science.1088805

Cited by 669 publications

(595 citation statements)

References 23 publications

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“…27). Using reporter genes that were targeted to either mitochondria or cytosol, Hagen demonstrated that NO inhibits respiration by inhibiting cytochrome c oxidase activity under hypoxic conditions, thereby permitting increased PHD activity as oxygen is redistributed to the cytosol 48 . Recently it has been reported that NO elicits a feedback regulatory mechanism between HIF1 and PHD2 (also known as EGLN1) 49 .…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…This feedback loop is possibly further supported by oxygen redistributed from mitochondria during the HIF-driven metabolic switch. Indeed, upon the inhibition of the mitochondrial respiration by nitric oxide, O2 redistribution was observed leading to the inactivation of HIF [38]. Thus, one can speculate that the HIF-mediated induction of the PHDs may allow setting the PHD-HIF system to a new steady state at lower pO2 levels ( Figure 2A).…”

Section: Transcriptional Feedbackmentioning

confidence: 97%

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

2016

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“…Indeed, it is reported that · NO can inhibit prolyl hydroxylase, leading to a possible hypoxic response under normoxic conditions (for example, (138)). On the other hand, · NO binding to cytochrome c oxidase appears to result in a redistribution of O 2 utilization resulting in an increase in prolyl hydroxylase activity and an inhibition of hypoxic responses (139). Thus, the effect of · NO on the hypoxic response is complex and equivocal and appears to be dependent on numerous factors including the concentration of · NO, the oxygen status of the cells and even the nature of the · NO donor used in the studies.…”

Section: C · No-heme and · No-metal Complexesmentioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

219

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α

Cited by 669 publications

References 23 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

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