Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury

Yang, Xiaosa; Yi, Tailong; Zhang, Sai; Xu, Zhongwei; Yu, Zhen; Sun, Hongtao; Yang, Cheng; Tu, Yue; Cheng, Shixiang

doi:10.1038/s41598-017-06088-0

Cited by 93 publications

(72 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of HIF-1α-associated signaling cascades, such as EPO pathway (Liu et al, 2006 ; Ryou et al, 2012 ) and VEGF pathway (Yin W. et al, 2017 ) in neurons could protect the brain from I/R damage through increasing microvascular density and/or restoring local blood flow and oxygen supply. Yang X. S. et al ( 2017 ) found that HIF-1α involved in necroptosis contributed to ischemic brain injury induced by OGD and MCAO. Inhibition of the 20S proteasomal activity can protects HIF-1α from degradation and provides neuroprotection in cerebral ischemia (Badawi and Shi, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

Zhang

Yang

Wang

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Neuregulin receptor degradation protein-1 (Nrdp1) is an E3 ubiquitin ligase that targets proteins for degradation and regulates cell growth, apoptosis and oxidative stress in various cell types. We have previously shown that Nrdp1 is implicated in ischemic cardiomyocyte death. In this study, we investigated the change of Nrdp1 expression in ischemic neurons and its role in ischemic neuronal injury. Primary rat cerebral cortical neurons and pheochromocytoma (PC12) cells were infected with adenoviral constructs expressing Nrdp1 gene or its siRNA before exposing to oxygen-glucose deprivation (OGD) treatment. Our data showed that Nrdp1 was upregulated in ischemic brain tissue 3 h after middle cerebral artery occlusion (MCAO) and in OGD-treated neurons. Of note, Nrdp1 overexpression by Ad-Nrdp1 enhanced OGD-induced neuron apoptosis, while knockdown of Nrdp1 with siRNA attenuated this effect, implicating a role of Nrdp1 in ischemic neuron injury. Moreover, Nrdp1 upregulation is accompanied by increased protein ubiquitylation and decreased protein levels of ubiquitin-specific protease 8 (USP8) in OGD-treated neurons, which led to a suppressed interaction between USP8 and HIF-1α and subsequently a reduction in HIF-1α protein accumulation in neurons under OGD conditions. In conclusion, our data support an important role of Nrdp1 upregulation in ischemic neuronal death, and suppressing the interaction between USP8 and HIF-1α and consequently the hypoxic adaptive response of neurons may account for this detrimental effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

Zhang

Yang

Wang

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In the middle cerebral artery occlusion (MCAO) model, therapeutic application of RIPK3 inhibitor GSK′872 or the pan-caspase inhibitor Z-VAD-FMK protected against ischemic brain injury. Furthermore, both GSK′872 and Ripk3 deficiency downregulated hypoxia-associated HIF-1α activation and cell death (119). The RIPK3 inhibitor dabrafenib protected against focal ischemic brain injury in mice (120).…”

Section: Necroptosis and Cardiovascular Diseasementioning

confidence: 97%

Necroptosis: a crucial pathogenic mediator of human disease

et al. 2019

View full text Add to dashboard Cite

Conflict of interest: AMKC is a cofounder of, is a stockholder of, and serves on the Scientific Advisory Board for Proterris, Inc., which develops therapeutic uses for carbon monoxide. AMKC also has a use patent (US 7,678,390) on CO. AMKC served as a consultant for Teva Pharmaceuticals in July 2018. The spouse of MEC is a cofounder of, is a shareholder of, and serves on the Scientific Advisory Board of Proterris, Inc.

show abstract

“…The effect of HIF on ischaemic brain may vary depending on the severity, duration of stroke as well as the time and amounts of HIF activation. The HIF can promote the transcription of multiple pro-survival proteins and exerts neuroprotection in ischaemic stroke ( Guo, 2017 ; Luo et al, 2017 ; Yang et al, 2017 ), but also involve in post-stroke inflammatory responses, apoptosis and BBB disruption ( Zhang et al, 2016 ).…”

Section: Hif and Phd Pharmacological Modulation In Ischaemic Strokementioning

confidence: 99%

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

Chen

Lai

Zhu³

et al. 2018

Front. Cell Dev. Biol.

197

137

View full text Add to dashboard Cite

Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.

show abstract

Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury

Cited by 93 publications

References 44 publications

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

Necroptosis: a crucial pathogenic mediator of human disease

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

Contact Info

Product

Resources

About