Role Of Nrf2 In Oxidative Stress And Toxicity PdfBy Tootie P. In and pdf 18.04.2021 at 01:29 5 min read
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- The role of Nrf2 in oxidative stress-induced endothelial injuries
Typically in aerobic metabolism, organic compounds such as nucleic acids, proteins and lipids can undergo structural damage by oxidative reactions. Various diseases such as cancer, diabetes, cardiovascular diseases and neurodegenerative clearly exemplify the chronic oxidative stress. Therefore, it is important to consider that at low and moderate ROS levels, it can, for example, act as signaling molecules that support cell proliferation and differentiation and activate survival pathways in response to stress.
Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes.
Nrf2 is located in the cytoskeleton, adjacent to Keap1. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases.
Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases. The vascular endothelium synthesizes and releases multiple biologically active molecules that modulate vascular structure, vasodilation, vasoconstriction, and thrombolysis and form a natural barrier that maintains internal homeostasis.
Vascular dysfunction elicits functional changes that lead to diminished nitric oxide bioavailability and the onset of cardiovascular disease Tousoulis et al. Endothelial dysfunction is associated with the pathogenesis of common diseases. Oxidative stress, hypoxia, and flow disturbances are important factors that are related to endothelial dysfunction Coleman et al.
Reactive oxygen species ROS are free radicals and reactive metabolites that contain oxygen molecules with unpaired electrons. ROS are essential signaling molecules in the regulation of vascular homeostasis Bachschmid et al. However, excessive ROS are a major cause of oxidative stress, the primary stimulus of vascular dysfunction. An initial consequence of increased ROS production is decreased NO availability, which results in decreased endothelium-dependent relaxation Rochette et al.
Excessive ROS generate large numbers of potentially harmful intermediates that cause cellular dysfunction and cell death resulting from alterations in metabolic activity, membrane structure, proteins, and DNA, which ultimately lead to imbalances between prooxidants and antioxidants that further result in aging and in numerous diseases. However, cellular evolution has enabled the development of adaptive antioxidant systems that scavenge excessive ROS.
There are two types of antioxidants: enzymatic and nonenzymatic or chemical. When antioxidant activity is disrupted, it is no longer possible to maintain appropriate redox balance. Nuclear factor-E2-related factor 2 Nrf2 , a transcription factor with a high sensitivity to oxidative stress, binds to antioxidant response elements AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes.
Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to AREs and the transcription of downstream target genes, including genes that encode antioxidants, detoxifying enzymes, antiapoptotic proteins, and proteasomes Niture et al. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2 signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries.
Moi et al. Under normal conditions, Nrf2 remains in the cytosol at a low concentration. Under stressful conditions, Nrf2 translocates into the nucleus and serves as a transcription factor to maintain cellular redox homeostasis.
Nrf2 plays an important role in cellular resistance to oxidative stress and exogenous toxic substances, and it is closely linked to inflammatory reactions, respiratory system diseases, cardiovascular diseases, and malignant tumors. It subsequently combines with AREs to trigger the transcription of more than endogenous protective genes, including i antioxidant genes, ii phase II detoxification enzyme genes, iii molecular chaperones, and iv anti-inflammatory co-stimulating genes.
These proteins play vital roles in strengthening cellular antioxidant defenses, and they protect tissues from harmful damage by exerting antitumor, anti-inflammatory, and antiapoptotic effects. Large amounts of data have demonstrated that the Nrf2—ARE pathway is one of the most powerful known intracellular antioxidative stress pathways. Nrf2 is the most potent member of the CNC transcription factor family, whose members share a highly conserved bZIP structure.
Studies have confirmed that Nrf2 is a polypeptide that contains amino acid residues and six domains, Neh1—Neh6 Nioi et al. Neh2 mediates the formation of heterodimers of Nrf2 and Keap1, the latter of which is the natural inhibitor of Nrf2 in the cytoplasm. Neh2 also has a hydrophilic domain that is rich in lysine residues and is essential for Keap1-dependent ubiquitin-mediated degradation of Nrf2. The Neh3 domain is located at the carboxyl terminus of Nrf2.
The Neh4 and Neh5 domains combine with another transcriptional coactivator, CBP, which is involved in the regulation of Nrf2 transcription activation. The Neh6 domain is involved in non-Keap1-dependent regulation and degradation of Nrf2 Fig. Because of the remarkable effects of Nrf2 on cell growth and apoptosis, DNA repair, inflammatory responses, and redox conditions, there is widespread interest in defining the factors and mechanisms that regulate its biological functions under physiological and pathological conditions.
The discovery that Keap1 is the key negative regulator of Nrf2 represents an important milestone and the culmination of more than a decade of study and investigation. Nrf2 and Keap1 protein secondary structures. A The protein structural domains of Nrf2 and Keap1. B The spatial patterns of interaction between Nrf2 and Keap1 under physiological conditions. C The spatial patterns of interaction between Nrf2 and Keap1 under oxidative stress conditions.
Citation: Journal of Endocrinology , 3; Under physiological conditions, Nrf2 is bound to its inhibitory protein, Keap1, and anchored to the actin cytoskeleton, which limits its transcriptional activity in the nucleus Kansanen et al.
The DGR domain contains six repetitive double-stranded glycine Gly sequences, the binding sites of both Nrf2 and actin. Ubiquitin ligase, which is also known as E3 ubiquitin ligase, connects ubiquitin molecules to the lysine residues of proteins. Typically, ubiquitin ligase forms many ubiquitin chains and is degraded by the 20S catalytic subunit of the proteasome. The IVR domain is rich in cysteine residues and is sensitive to electrophiles and external oxidation stressors.
When it is exposed to oxidative stress, the IVR domain induces conformational changes that lead to the dissociation of Nrf2 from Keap1 Fig. Keap1 is rich in cysteine residues, and there are 27 cysteines in human Keap1. Some of these cysteine residues are located near basic residues and are therefore prone to stimulation by electrophiles and oxidants.
The modification of these cysteine residues by electrophiles is known as the cysteine code. The cysteine code hypothesis states that different Nrf2 activators act on different Keap1 cysteines.
Cysteine modifications lead to conformational changes in Keap1, which disrupts the interactions between the Nrf2 DLG domains and the Keap1 Kelch domains, thereby inhibiting the polyubiquitination of Nrf2. The functional importance of Cys, Cys, and Cys has been established: Cys and Cys are required for the suppression of Nrf2, and Cys is required for its activation Kansanen et al.
The sequences are activated by a variety of electrophiles and oxidants, and they trigger the expression of phase II detoxification enzymes and antioxidant enzymes. Nrf2 is the most important activator of AREs. Under oxidative stress conditions, Nrf2 dissociates from Keap1, translocates into the nucleus, combines with the Maf protein to form a heterodimer, and recognizes the appropriate ARE sequence. ARE-mediated gene transcription is subsequently activated.
The Nrf2—ARE pathway inhibits Nrf2 degradation mediated by the ubiquitin proteasome, stabilizes cytoplasmic Nrf2 protein concentrations, promotes Nrf2 nuclear translocation, and increases Nrf2 transcriptional activity.
The activation of Nrf2 forms a positive feedback loop. Nrf2 is a key transcription factor that regulates cells in response to invaders and oxidative damage. Degradation and inhibition of Nrf2 causes cells to become more sensitive, which then leaves them vulnerable to damage, even in low-stress environments. The Nrf2—ARE pathway is involved in a wide range of cellular protective functions, because it has antitumor, antioxidant, antiapoptotic, anti-inflammatory, and anti-atherosclerotic effects.
Aside from endothelial injuries caused by oxidative stress, cellular antioxidant defenses depend primarily on Nrf2 dissociation from Keap1 and its subsequent translocation to the nucleus, where the activation of antioxidant genes occurs.
Under physiological conditions, a homodimer composed of two Keap1 molecules combines with one Nrf2 molecule, which serves as an adaptive substrate for E3 ubiquitin ligase and promotes Nrf2 ubiquitination and 26S proteasome degradation Fig. Nrf2 regulation depends primarily on the interaction between Nrf2 and Keap1.
In the dissociation model, ROS and electrophiles result in the oxidation of Keap1 cysteine residues, which in turn causes a conformational change and the subsequent dissociation of Nrf2 from Keap1.
This is the most commonly accepted explanation of how Nrf2 activation occurs Bryan et al. Because the Keap1 binding site remains occupied by Nrf2, newly produced Nrf2 molecules are unable to bind with Keap1, so they instead enter the nucleus and combine with AREs.
This ultimately results in the expression of downstream target genes Kansanen et al. Two models to describe the interaction between Nrf2 and Keap1 under stress conditions.
A The Nrf2—Keap1 complex under physiological conditions. B The Nrf2—Keap1 complex under oxidative stress conditions. It is well known that the Michael addition reaction is involved in Nrf2 activation.
Many chemical and phytochemical agents react with thiol groups and induce the phase II response through their reactivity with critical cysteine thiols of Keap1.
Liu et al. Chemopreventive flavonoids that promote the expression of NQO1 Wang et al. In contrast, tetrahydrocurcumin, which lacks a Michael reaction acceptor, was shown to have no effect on HO-1 expression, ARE activation, or vascular smooth muscle cell VSMC growth inhibition Pae et al.
Phosphorylation plays a crucial role in the regulation of most transcription factors. Multiple protein kinases are involved in Nrf2 regulation as a result of their participation in Nrf2 phosphorylation. Other protein partners, such as p21 and caveolin-1, as well as microRNA molecules such as microRNA, , and a, have been shown to affect Nrf2 activation and nuclear translocation by different means Bryan et al.
Cys and Cys residues in Keap1 are required for the suppression of Nrf2, and Cys is required for the activation of Nrf2 by electrophiles and ROS. Numerous reports indicate that PKC has the ability to activate Nrf2 both inside and outside of cells.
PKC-mediated Nrf2 phosphorylation may be a key step in Nrf2 nuclear translocation. Rodriguez-Ramiro et al. Utilizing ERK- and pspecific inhibitors reduces Nrf2 nuclear translocation. The PI3K—Akt signaling pathway is involved in the regulation of cell migration, proliferation, and survival.
Additional research has shown that the activation of PI3K may result in cytoskeletal reorganization Koriyama et al. CK2 is also involved in the transcriptional regulation of Nrf2. CK2 interacts with two phosphorylated forms of Nrf2, specifically Nrf and Nrf, the latter of which has transcription activity, which makes it easier for it to degrade Pi et al.
Additionally, glycogen synthesis kinase 3 GSK3; Chowdhry et al. Tyrosine kinase Fyn is an Nrf2 suppressor. There is a large amount of evidence to suggest that endothelial dysfunction is the initial step in the pathogenesis of several cardiovascular diseases.
Oxidative stress induced by hypertension, hypercholesterolemia, diabetes mellitus, aging, obesity, and smoking strongly correlates with endothelial dysfunction. This results in the generation of more ROS within vessels, which initiates a vicious cycle that impairs endothelial function.
Decreases in NO production appear to be related to diminished activity of the PI3K—Akt pathway under pathologic conditions. Additionally, decreased levels of l -arginine, which acts as a substrate for the eNOS, contribute to reduced NO production.
ROS activate membrane oxidases, which results in an increased level of asymmetric dimethylarginine, a derivative of arginine that competes for the active sites on eNOS and l -arginine transporters Chien et al.
Oxidative Stress and Disease
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The role of Nrf2 in oxidative stress-induced endothelial injuries
Oxidative stress resulting from environmental exposures is associated with a variety of human diseases ranging from chemical teratogenesis to cardiovascular and neurodegenerative diseases. Developing animals appear to be especially sensitive to chemicals causing oxidative stress. The expression and inducibility of antioxidant defenses are critical factors affecting susceptibility to oxidants at these early life stages, but the ontogenic development of these responses in embryos is not well understood. In adult animals, oxidants initiate an anti-oxidant response by activating NF-E2-related factor 2 NRF2 and related proteins, which bind to the anti-oxidant response element and activate transcription of genes such as glutathione S-transferases, NAD P H-quinone oxidoreductase, glutamyl-cysteine ligase, and superoxide dismutase. The overall objective of the research proposed here is to elucidate the mechanisms by which vertebrate embryos respond to oxidative stress during development.
The nuclear factor erythroid 2–related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure.