The redox state of glutathione regulates the hypoxic induction of HIF-1

Tajima, Masamichi; Kurashima, Yukiko; Sugiyama, Kenji; Ogura, Tsutomu; Sakagami, Hiroshi

doi:10.1016/j.ejphar.2009.01.026

Cited by 58 publications

(38 citation statements)

References 33 publications

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“…Finally, the concomitant presence of oxidative stress and O 2 deprivation raises the question of whether hypoxia-induced factor (HIF) pathways modulate the cellular response to hypoxia-induced oxidative stress (Fandrey and Gassmann, 2009). It has been suggested that increased oxidative stress may increase HIF-1 activity (Tajima et al, 2009), which in turn may decrease GSH biosynthesis (Jackson and Gupta, 2010). Such hypothesis requires further investigation in order to understand the contribution of HIF-1 to changes in GSH content in RBE4 monolayers during O 2 deprivation injury.…”

Section: Discussionmentioning

confidence: 99%

Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown

Ahmad

Gassmann

Ogunshola

2012

Microvascular Research

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The blood-brain barrier (BBB) is a cellular barrier formed by specialized brain endothelial cells under the influence of astrocytes and pericytes. Among the several stress factors known to induce BBB breakdown, hypoxia is probably the most represented but also the least understood. Recent evidence of oxidative stress occurring during hypoxia/ischemia situation raises its possible contribution to barrier breakdown. In this study, we investigated the relevance of oxidative stress in hypoxia-induced barrier disruption. Prolonged hypoxic exposure induced radical oxygen species (ROS) formation and induced glutathione oxidation. Such effects were accentuated under extreme O(2) deprived environment. Prooxidant treatment significantly disrupted barrier function under normal conditions, whereas anti-oxidant treatment contributed to maintain better barrier function and cell survival in an O(2)-reduced environment. In addition, the endothelial response to oxidative stress appeared modulated by the presence of astrocytes and pericytes, thus explaining some of the beneficial contribution of these cells as previously described. Taken together, this study highlights the importance of oxidative stress signaling at the barrier. In addition, cells of the neurovascular compartment differentially modulate ROS levels and also regulate barrier function. Thus, use of radical scavengers may be useful to support barrier function following stroke injury.

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Section: Discussionmentioning

confidence: 99%

Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown

Ahmad

Gassmann

Ogunshola

2012

Microvascular Research

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“…41 GSH was found to reduce HIF-1 binding activity and HIF-1-dependent promoter activity in squamous cell carcinoma cells in a dose-dependent manner. 40 Plasmin-mediated cleavage of the HRG backbone is also required to release the antiangiogenic HRR/PRR fragment. The data here might suggest that generally reduction, and not proteolysis, occurs first given that sufficient quantities of reduced HRG were present to allow the crystal of the N2 domain to form, but this is not definitive.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown to prohibit ischemia-induced lung angiogenesis by sequestering of reactive oxygen species. 40 GSH also regulates induction of hypoxia-inducible factor 1 (HIF-1), which controls the expression of proangiogenic genes such as VEGF. 41 GSH was found to reduce HIF-1 binding activity and HIF-1-dependent promoter activity in squamous cell carcinoma cells in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel b-sheet wrapped around a 5-turn a-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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“…114,115 Non-enzymatic antioxidants include ascorbate, tocopherols, glutathione, bilirubin and uric acid and scavenge OH and other free radicals. 116 Extracellular SOD, the major vascular SOD, is produced and secreted by vascular smooth muscle cells and binds to glycosaminoglycans in the vascular extracellular matrix and regulates oxidant status in the vascular interstitium. 114,115 Decreased antioxidant capacity promotes cellular oxidative stress and has been implicated in cardiovascular and renal oxidative damage associated with hypertension.…”

Section: Vascular Antioxidant Systemsmentioning

confidence: 99%

Reactive oxygen species and vascular biology: implications in human hypertension

2010

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Increased vascular production of reactive oxygen species (ROS; termed oxidative stress) has been implicated in various chronic diseases, including hypertension. Oxidative stress is both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, vessels and possibly the immune system. Compelling experimental and clinical evidence indicates the importance of the vasculature in the pathophysiology of hypertension and as such much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular, renal and neural ROS is a family of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), including the prototypic Nox2 homolog-based NADPH oxidase, as well as other Noxes, such as Nox1 and Nox4. Nox-derived ROS is important in regulating endothelial function and vascular tone. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in hypertension. Despite a plethora of data implicating oxidative stress as a causative factor in experimental hypertension, findings in human hypertension are less conclusive. This review highlights the importance of ROS in vascular biology and focuses on the potential role of oxidative stress in human hypertension.

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The redox state of glutathione regulates the hypoxic induction of HIF-1

Cited by 58 publications

References 33 publications

Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown

Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Reactive oxygen species and vascular biology: implications in human hypertension

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