scholarly journals Caveolae, CAVIN1, and lipid peroxidation mediate the oxidative stress response

2021 ◽  
Author(s):  
Yeping Wu ◽  
Ye-Wheen Lim ◽  
David A Stroud ◽  
Nick Martel ◽  
Thomas E. Hall ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Quantitative Proteomics ◽  
Cellular Response ◽  
Direct Interaction ◽  
Related Factor ◽  
The Novel ◽  
Biological Functions ◽  
Structural Protein ◽  
Mechanistic Studies

Caveolae have been linked to a number of biological functions but their precise roles are as yet unclear. Here we have undertaken an unbiased approach to characterize the cellular proteome regulated by the caveolar structural protein, CAVIN1, by utilizing genome-edited cells together with whole cell quantitative proteomics. Pathway analysis identified the cellular response to oxidative stress as the most significant effect of CAVIN1 loss. Functional experiments showed that sensitivity to oxidative stress was compromised in CAVIN1-null cells and zebrafish knockout lines. Mechanistic studies identified oxidative stress-triggered lipid peroxidation as the novel upstream mechanism for caveolar disassembly and release of CAVIN1. Disassembly of caveolae allows direct interaction of CAVIN1 and nuclear factor erythroid 2-related factor 2 (NRF2), a key antioxidant activator. This causes NRF2 sequestration and degradation in the cytosol, inhibiting its transcriptional function in the nucleus. Thus caveolae, via lipid peroxidation and CAVIN1 release, regulate cellular susceptibility to oxidative stress-induced ferroptosis.

Caveolae respond to acute oxidative stress through membrane lipid peroxidation, cytosolic release of CAVIN1, and downstream regulation of NRF2

2021 ◽  
Author(s):  
Yeping Wu ◽  
Ye-Wheen Lim ◽  
David Stroud ◽  
Nick Martel ◽  
Thomas Hall ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Cultured Cells ◽  
Direct Interaction ◽  
Antioxidant Response ◽  
Membrane Lipid ◽  
Wound Response ◽  
Biological Functions ◽  
Structural Protein ◽  
Major Pathway

Abstract Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation (LPO) and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to LPO-induced ferroptosis. Thus, caveolae, via LPO and CAVIN1 release, maintain cellular susceptibility to oxidative stress-induced cell death demonstrating a crucial role for this enigmatic organelle in cellular homeostasis and wound response.

scholarly journals SLC7A11 Reduces Laser-Induced Choroidal Neovascularization by Inhibiting RPE Ferroptosis and VEGF Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaohuan Zhao ◽  
Min Gao ◽  
Jian Liang ◽  
Yuhong Chen ◽  
Yimin Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Cell Viability ◽  
Laser Treatment ◽  
Choroidal Neovascularization ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Rpe Cells ◽  
Age Related

In age-related macular degeneration (AMD), one of the principal sources of vascular endothelial growth factor (VEGF) is retinal pigment epithelium (RPE) cells under hypoxia or oxidative stress. Solute carrier family 7 member 11 (SLC7A11), a key component of cystine/glutamate transporter, regulates the level of cellular lipid peroxidation, and restrains ferroptosis. In our study, we assessed the role of SLC7A11 in laser-induced choroidal neovascularization (CNV) and explored the underlying mechanism. We established a mouse model of CNV to detect the expression level of SLC7A11 and VEGF during disease progression. We found the expression of the SLC7A11 protein in RPE cells peaked at 3 days after laser treatment, which was correlated with the expression of VEGF. Intraperitoneal injection of SLC7A11 inhibitor expanded the area of CNV. We examined functional proteins related to oxidative stress and Fe2+ and found laser-induced ferroptosis accompanied by increased Fe2+ content and GPX4 expression in the RPE-choroidal complex after laser treatment. We verified the expression of SLC7A11 in the ARPE19 cell line and the effects of its inhibitors on cell viability and lipid peroxidation in vitro. Application of SLC7A11 inhibitor and SLC7A11 knockdown increased the level of lipid peroxidation and reduced the cell viability of ARPE19 which can be rescued by ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1). Conversely, SLC7A11 overexpression induced resistance to erastin or RSL3-induced ferroptosis. Moreover, we tested the possible regulatory transcription factor NF-E2-related factor 2 (NRF2) of SLC7A11 by Western blot. Knock-down of NRF2 decreased the expression of SLC7A11. Our study suggests that SLC7A11 plays a key role in the laser-induced CNV model by protecting RPE cells from ferroptosis. SLC7A11 provides a new therapeutic target for neovascular AMD patients.

Abstract 28: Carboxyalkyl-pyrrole Phosphatidylethanolamine Adducts Are Present In Vivo And Induce Platelet Activation Via Toll-like Receptor

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Sudipta Biswas ◽  
Soumya Panigrahi ◽  
Alejandro Zimman ◽  
Eugene Podrez
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Biological Activities ◽  
Direct Interaction ◽  
Covalent Modification ◽  
Downstream Signaling

A prothrombotic state and increased platelet reactivity are common in pathophysiological conditions associated with oxidative stress. Lipid peroxidation, a major consequence of oxidative stress generates highly reactive products capable of modifying autologous proteins as well as lipids. Hydroxy-ω-oxoalkenoic acids and their carboxyalkylpyrrole (CAP) protein adducts are recently described products of lipid peroxidation with strong biological activity mediated by Toll like receptors (TLR). Phosphatidylethanolamine (PE) is the second most abundant phospholipid in the living organisms. While recent studies suggest that PE is a major target for covalent modification by reactive products of lipid peroxidation, the presence of such products in vivo, their biological activities and receptors involved are not established. We now report that CAP-PE adducts are present in vivo in circulation and are significantly elevated in plasma of hyperlipidemic apoE-/- mice. In vitro experiments demonstrated that CAP-PE adducts induce platelet integrin αIIbβ3 activation, P-selectin expression and promote platelet aggregation. Multiple complimentary approaches demonstrated that platelet activation by CAP-PE is mediated by TLR2 and TLR1. Furthermore, direct interaction of CAP-PE and TLR2 was demonstrated. CAP-PE induced assembly of TLR2/TLR1 receptor complex in platelets leading to downstream signaling via MyD88/TIRAP-dependent pathway. CAPs-PE induced signaling included phosphorylation and activation of IRAK4 and subsequent activation of TRAF6, Src family kinase, Syk and PLCγ2. Thus, our study identified carboxyalkylpyrrole adducts of phosphatidylethanolamine as novel end products accumulating in circulation in hyperlipidemia that can induce platelet activation via innate immunity signaling pathway.

scholarly journals Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress

2015 ◽  
Vol 43 (4) ◽  
pp. 657-662 ◽  
Author(s):  
Fiona E. Mutter ◽  
B. Kevin Park ◽  
Ian M. Copple
Keyword(s):  
Oxidative Stress ◽  
Mammalian Cells ◽  
Direct Interaction ◽  
Experimental Models ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Oxidative Stresses ◽  
Therapeutic Drugs ◽  
Numerous Cell ◽  
And Oxidative Stress

Beyond specific limits of exposure, chemical entities can provoke deleterious effects in mammalian cells via direct interaction with critical macromolecules or by stimulating the accumulation of reactive oxygen species (ROS). In particular, these chemical and oxidative stresses can underpin adverse reactions to therapeutic drugs, which pose an unnecessary burden in the clinic and pharmaceutical industry. Novel pre-clinical testing strategies are required to identify, at an earlier stage in the development pathway, chemicals and drugs that are likely to provoke toxicity in humans. Mammalian cells can adapt to chemical and oxidative stress via the action of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which up-regulates the expression of numerous cell defence genes and has been shown to protect against a variety of chemical toxicities. Here, we provide a brief overview of the Nrf2 pathway and summarize novel experimental models that can be used to monitor changes in Nrf2 pathway activity and thus understand the functional consequences of such perturbations in the context of chemical and drug toxicity. We also provide an outlook on the potential value of monitoring Nrf2 activity for improving the pre-clinical identification of chemicals and drugs with toxic liability in humans.

scholarly journals Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

2021 ◽  
Vol 22 (14) ◽  
pp. 7434
Author(s):  
Nadun C. Karunatilleke ◽  
Courtney S. Fast ◽  
Vy Ngo ◽  
Anne Brickenden ◽  
Martin L. Duennwald ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Cellular Response ◽  
Rational Design ◽  
Oxidative Stress Response ◽  
Full Length ◽  
Related Factor ◽  
Creb Binding Protein ◽  
Physiological Importance ◽  
Kelch Domain

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor alpha (RXRα), Nrf2 mediates the transcription of cytoprotective genes critical for removing toxicants and preventing DNA damage, thereby playing a significant role in chemoprevention. Dysregulation of Nrf2 is linked to tumorigenesis and chemoresistance, making Nrf2 a promising target for anticancer therapeutics. However, despite the physiological importance of Nrf2, the molecular details of this protein and its interactions with most of its targets remain unknown, hindering the rational design of Nrf2-targeted therapeutics. With this in mind, we used a combined bioinformatics and experimental approach to characterize the structure of full-length Nrf2 and its interaction with Keap1. Our results show that Nrf2 is partially disordered, with transiently structured elements in its Neh2, Neh7, and Neh1 domains. Moreover, interaction with the Kelch domain of Keap1 leads to protection of the binding motifs in the Neh2 domain of Nrf2, while the rest of the protein remains highly dynamic. This work represents the first detailed structural characterization of full-length Nrf2 and provides valuable insights into the molecular basis of Nrf2 activity modulation in oxidative stress response.

scholarly journals Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Wenpeng Cui ◽  
Xu Min ◽  
Xiaohong Xu ◽  
Bing Du ◽  
Ping Luo
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cellular Response ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nuclear Factor ◽  
Urinary Protein Level ◽  
Nrf2 Activation ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies.

scholarly journals microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4338-4348 ◽  
Author(s):  
Carolyn Sangokoya ◽  
Marilyn J. Telen ◽  
Jen-Tsan Chi
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Stress Tolerance ◽  
Sickle Cell ◽  
Cellular Response ◽  
Genetic Mutation ◽  
Related Factor ◽  
Cell Disease ◽  
Erythroid Progenitor ◽  
Oxidative Stress Tolerance

Abstract Although individuals with homozygous sickle cell disease (HbSS) share the same genetic mutation, the severity and manifestations of this disease are extremely heterogeneous. We have previously shown that the microRNA expression in normal and HbSS erythrocytes exhibit dramatic differences. In this study, we identify a subset of HbSS patients with higher erythrocytic miR-144 expression and more severe anemia. HbSS erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype remains unknown. This study reveals that miR-144 directly regulates nuclear factor-erythroid 2-related factor 2, a central regulator of cellular response to oxidative stress, and modulates the oxidative stress response in K562 cell line and primary erythroid progenitor cells. We further demonstrate that increased miR-144 is associated with reduced NRF2 levels in HbSS reticulocytes and with decreased glutathione regeneration and attenuated antioxidant capacity in HbSS erythrocytes, thereby providing a possible mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients. Taken together, our findings suggest that erythroid microRNAs can serve as genetic modifiers of HbS-related anemia and can provide novel insights into the clinical heterogeneity and pathobiology of sickle cell disease.

CHARACTERISTICS AND THERAPEUTIC EFFECTS OF THE NOVEL FREE RADICAL SCAVENGER – EDARAVONE

2020 ◽  
Vol 04 (05) ◽  
pp. 17-20
Author(s):  
Mirza Mikayil Aliyev ◽  
◽  
Ulduz Yunis Safarova ◽  
Shafiqa Jahangir Jafarova ◽  
◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Arachidonic Acid ◽  
Free Radical ◽  
Hydroxyl Radicals ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Therapeutic Effects ◽  
The Novel ◽  
Prostacyclin Production

Edaravone is the first free radical scavenger which approved clinically and has an ability to decrease the level of free radicals in cells. Edaravone is a strong antioxidant, which can protect different cells (e.g. endothelial cells) against damage by ROS by inhibiting the lipoxygenase metabolism of arachidonic acid, by trapping hydroxyl radicals, by increasing prostacyclin production, by inhibiting alloxan-induced lipid peroxidation, etc. Because of that, Edaravone is used in treatment of diseases which are associated with oxidative stress. Key words: edaravone, free radical, antioxidant, neuroprotective agent, oxidative stress

Sign in / Sign up

Export Citation Format

Share Document