Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells

BelAiba, Rachida S.; Djordjevic, Talija; Bonello, Steve; Flügel, Daniela; Hess, John; Kietzmann, Thomas; Görlach, Agnes

doi:10.1515/bc.2004.019

Cited by 109 publications

(72 citation statements)

References 33 publications

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“…When catalase is overexpressed, stabilization of HIF1α disappears, indicating that H 2 O 2 is required for the response 36 . Angiotensin II and thrombin can stimulate generation of free radical species and mimic the effects of hypoxia to upregulate HIF1α levels and activity.…”

Section: Free Radical Regulation Of Hif1 Under Aerobic 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 Aerobic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Oxidative stress is a non-hypoxic stimulus that induces HIF-1 activation. For instance, growth factor, thrombin or insulin are able to promote the HIF-1 response following stimulation of cellular ROS generation [10,27,28]. These responses were inhibited by antioxidants or overexpression of redox-modifying enzymes, showing that an antioxidant state reduces levels of free radicals to limit activation of the HIF pathway, whereas elevated cellular levels of oxidative radicals promote the pathway.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1 can also respond to a variety of non-hypoxic stimuli, including vasoactive peptides, cytokine and hormones [10][11][12]. These stimuli can initiate ROS production which then can activate the HIF-1 cascade.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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Cyanide produces degeneration of the nervous system in which different modes of cell death are activated in the vulnerable brain areas. In brain, the mechanism underlying the cell death is not clear. In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide-treated cells exhibited a time-and concentration-dependent apoptosis that was caspase-independent. Cyanide induced a rapid surge of intracellular reactive oxygen species (ROS) generation, followed by p38 mitogen-activated protein kinase (MAPK) activation and nuclear accumulation of hypoxia-inducible factor-1α (HIF-1α). Activation of p38 MAPK and HIF-1α accumulation were attenuated by N-acetyl-L-cysteine (antioxidant), catalase (hydrogen peroxide scavenger) or a selective p38 MAPK inhibitor (SB203580). Cyanide activated the hypoxia response element (HRE) promoter, which was also blocked by the antioxidants and SB203580. HRE activation was followed by increased BNIP3 gene transcription, as reflected by elevated BNIP3 mRNA and protein levels. BNIP3 upregulation was reduced by selective RNAi knockdown of HIF-1α. Overexpression of BNIP3 produced mitochondrial dysfunction (reduced membrane potential), caspase-independent apoptosis, and sensitization of the cells to cyanideinduced toxicity. Expression of a dominant negative mutant or RNAi knockdown of BNIP3 protected the cells from cyanide. It was concluded that cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondrial-mediated death.

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“…Details of the constructs have been published previously (8,12,29). The catalase-containing plasmid was a kind gift of Thomas Kietzmann (University of Kaiserslautern, Germany) (30,31). The SOCS3 plasmid and the empty vector control were a kind gift from Julia Strebovsky (University of Heidelberg, Germany).…”

Section: Transfection Experimentsmentioning

confidence: 99%

Sustained Submicromolar H2O2 Levels Induce Hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

Millonig

Ganzleben

Peccerella

et al. 2012

Journal of Biological Chemistry

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Background: Hepcidin, the systemic iron regulator, is induced during inflammation and leads to low circulating and increased intracellular iron levels. Results: (Patho)physiologically relevant H 2 O 2 levels up-regulate hepcidin via STAT3 in cultured liver cells. Conclusion: Intracellular and extracellular H 2 O 2 acts similarly to IL-6 on hepcidin up-regulation and requires a functional STAT3-binding site. Significance: H 2 O 2 is an important link between inflammation and iron metabolism.

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Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells

Cited by 109 publications

References 33 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Sustained Submicromolar H2O2 Levels Induce Hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

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