NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway

Guo, Xiaoyun; Hong, Siqi; He, Hui; Zeng, Yachang; Chen, Yi; Mo, Xiaoliang; Li, Jing; Li, Lei; Steinmetz, Rachel N.; Liu, Qinghang

doi:10.1016/j.freeradbiomed.2020.07.031

Cited by 42 publications

(23 citation statements)

References 64 publications

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“…Indeed, inhibition of NFkB promoted cell death after prolonged TNFa stimulation, which was partially blocked by the RIPK1 inhibitor Nec-1s, consistent with our previous results (14). In contrast to the severe cardiac phenotype in our Tab2-deficient mice, cardiac-specific ablation of the major NFkB subunit RelA (NFkB-p65) showed no overt cardiac abnormalities (56,57). Similarly, mice lacking another NFkB subunit Nfkb1 (NFkB-p50) exhibited no detectable cardiac phenotype at baseline (58).…”

Section: Discussionsupporting

confidence: 90%

“…NFkB Luciferase activity assays. NFkB luciferase reporter assay was performed as we previously described (57). Cells transduced with adenoviral vectors encoding the NFkB luciferase reporter were washed in PBS and then resuspended in lysis buffer (100 mM KH2PO4, pH 7.8, 0.5% NP-40, and 1 mM DTT).…”

Section: Histological Analysis and Immunofluorescence Staining Mouse Hearts Were Fixed In 10%mentioning

confidence: 99%

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TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

Yin¹,

Guo²,

Chen³

et al. 2022

Journal of Clinical Investigation

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Mutations in TAB2 (transforming growth factor β activated kinase 1 binding protein 2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing RIPK1 (receptor-interacting protein kinase 1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling following pathological stress. In cardiomyocytes, deletion of TAB2, but not its close homologue TAB3, promoted TNFa-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knock-in effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrate that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

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Section: Discussionsupporting

confidence: 90%

Section: Histological Analysis and Immunofluorescence Staining Mouse Hearts Were Fixed In 10%mentioning

confidence: 99%

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

Yin¹,

Guo²,

Chen³

et al. 2022

Journal of Clinical Investigation

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“…For instance, ROS is believed to be involved in necrotic cardiomyocyte death via MPTP opening that is deemed as a main cause of the necrotic cell death rather than just inducing apoptosis [ 95 ]. Another report has shown that in cardiomyocytes, ROS activate NF- κ B and thereby inhibit the Nrf2-ARE pathway to promote oxidative stress-induced necrosis [ 166 ]. In addition to working as signaling molecules in the cell death pathways, ROS also initiate cell death through directly damaging various macromolecules like proteins, DNA, and lipids [ 67 ].…”

Section: Pathways Through Which Oxidative Stress Causes Myocardial Reperfusion Injurymentioning

confidence: 99%

Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments

Xiang

Xin

et al. 2021

Oxidative Medicine and Cellular Longevity

142

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Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy.

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“…Previous studies have revealed that NRF2 plays a critical protective role in response to oxidative stress-induced cell death such as apoptosis, ferroptosis and necrosis [ 36 – 39 ]. Here, we investigated whether NRF2 protected vascular endothelial cells against CuONPs-induced cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

Du²,

Mao

et al. 2022

J Nanobiotechnol

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NRF2 is the key antioxidant molecule to maintain redox homeostasis, however the intrinsic mechanisms of NRF2 activation in the context of nanoparticles (NPs) exposure remain unclear. In this study, we revealed that copper oxide NPs (CuONPs) exposure activated NRF2 pathway in vascular endothelial cells.NRF2knockout remarkably aggravated oxidative stress, which were remarkably mitigated by ROS scavenger. We also demonstrated that KEAP1 (the negative regulator of NRF2) was not primarily involved in NRF2 activation in thatKEAP1knockdown did not significantly affect CuONPs-induced NRF2 activation. Notably, we demonstrated that autophagy promoted NRF2 activation as evidenced by thatATG5knockout or autophagy inhibitors significantly blocked NRF2 pathway. Mechanically, CuONPs disturbed ubiquitin–proteasome pathway and consequently inhibited the proteasome-dependent degradation of NRF2. However, autophagy deficiency reciprocally promoted proteasome activity, leading to the acceleration of degradation of NRF2 via ubiquitin–proteasome pathway. In addition, the notion that the reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome was further proven in a CuONPs pulmonary exposure mice model. Together, this study uncovers a novel regulatory mechanism of NRF2 activation by protein degradation machineries in response to CuONPs exposure, which opens a novel intriguing scenario to uncover therapeutic strategies against NPs-induced vascular injury and disease.Graphical Abstract

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NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway

Cited by 42 publications

References 64 publications

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments

Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

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