The pivotal role of nuclear factor erythroid 2-related factor 2 in diabetes-induced endothelial dysfunction

Karan, Amin; Bhakkiyalakshmi, Elango; Jayasuriya, Ravichandran; Sarada, Dronamraju V. L.; Ramkumar, Kunka Mohanram

doi:10.1016/j.phrs.2019.104601

Cited by 45 publications

(22 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is the opening line of proof highlighting the role of RA-mediated Nrf2 activation in endothelial cells. Nrf2 is a chief regulator of the cellular stress response, and the activation of Nrf2 by small molecules has shown protective effects against the development of ED both in vitro and in vivo studies [ 16 ]. In the present study, RA activated Nrf2, thereby triggering its downstream regulations, including HO-1, NQO1, GPx, and CAT.…”

Section: Discussionmentioning

confidence: 99%

“…When the cells encounter oxidative stress or electrophiles, Nrf2 detaches from the Nrf2-Keap1 complex and translocates to the nucleus that activates the gene expression of antioxidant responsive element (ARE) to sustain cellular redox homeostasis [ 15 ]. In recent years, activation of Nrf2 by small molecules have been demonstrated as a new promising therapeutic approach for counteracting endothelial apoptosis [ 16 – 19 ]. It is interesting to note that Nrf2 is reported to associate with the UPR sensor called pancreatic endoplasmic reticulum kinase [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…We have developed a high-throughput screening system based on luciferase complementation to screen Nrf2 activators and demonstrated its role against oxidative and cytokine stress in pancreatic beta cells through Nrf2 activation [ 21 – 25 ]. Few Nrf2 activators showed promising results against hyperglycemia-induced endothelial dysfunction (ED) [ 16 ]. Earlier, we reported quercetin, a potent Nrf2 activator that showed a cytoprotective effect on endothelial cells against ER stress-induced ED [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells

Amin

Rajagru

Sarkar

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) plays a key role in the folding, modification, and trafficking of proteins. When the homeostasis of the ER is disturbed, un/misfolded proteins accumulate in the ER which leads to ER stress. Sustained ER stress results in apoptosis, which is associated with various diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor in redox homeostasis by regulating various genes associated with detoxification and cell-protective mechanisms. We found that Rosolic acid (RA) treatment dose-dependently activates Nrf2 in endothelial cells using the enzyme fragment complementation assay. The cytoprotective role of RA against ER stress-induced endothelial apoptosis and its molecular mechanism was explored in the present study. The Nrf2 and its target genes, as well as ER stress marker expressions, were measured by qPCR in ER stress-exposed endothelial cells. The contribution of Nrf2 in RA-mediated defense mechanism in endothelial cells was established by knockout studies using Nrf2-CRISPR/Cas9. The treatment with RA to ER stress-induced endothelial cells exhibited activation of Nrf2, as demonstrated by Nrf2 translocation and reduction of ER stress markers. We found that the Nrf2 knockout sensitized the endothelial cells against ER stress, and further, RA failed to mediate its cytoprotective effect. Proteomic studies using LC-MS/MS revealed that among the 1370 proteins detected, we found 296 differentially regulated proteins in ER stress-induced endothelial cells, and RA administration ameliorated 71 proteins towards the control levels. Of note, the ER stress in endothelial cells was attenuated by the treatment with the RA, suggesting the role of the Nrf2 activator in the pathological conditions of ER stress-associated diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells

Amin

Rajagru

Sarkar

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Of note, Nrf2 activity decreases with age [14][15][16][17]. Nrf2 ameliorates endothelial dysfunction in diabetes and under condition of oxidative stress [18] and increases the amount of bioavailable nitric oxide (NO), which is a major vasodilator [19]. Oxidative stress is also known to induce vascular senescence [20], which is important for vascular aging.…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging

et al. 2020

View full text Add to dashboard Cite

Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (−617C>A; hereafter called SNP−617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP−617 affects vascular stiffness with aging in apparently healthy people. Methods Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP−617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP−617 on other cardiovascular and blood test measurements.

show abstract

“…The Nrf2 signaling pathway is required to regulate the expression of antioxidant and antiapoptosis-related enzymes, and this pathway plays a considerable role in maintaining antioxidant homeostasis [36,37]. Under stress conditions, the newly synthesized Nrf2 translocates to the nucleus and subsequently activates downstream antioxidant genes to inhibit ROS production [38]. As shown in the present study, farrerol protected cells from H 2 O 2 -mediated oxidative stress by inducing the nuclear translocation of Nrf2 (Figures 4(a)-4(c)) and increasing its downstream like HO-1, NQO-1, and GCLM (Figures 4(d)-4(g) and 4(i)-4(k)).…”

mentioning

confidence: 99%

Farrerol Enhances Nrf2‐Mediated Defense Mechanisms against Hydrogen Peroxide‐Induced Oxidative Damage in Human Retinal Pigment Epithelial Cells by Activating Akt and MAPK

Yang

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Oxidative stress of the retinal pigment epithelium (RPE) is an essential element contributing to the progression of age-related macular degeneration (AMD). Notably, the activation of Nrf2 is regarded as an effective strategy for controlling oxidation. The novel 2,3-dihydroflavonoid compound farrerol, which is extracted from Rhododendron, possesses antioxidant properties. In this study, we investigated the mechanism by which farrerol protects against oxidative damage mediated by hydrogen peroxide (H2O2) in adult retinal pigment epithelial cell line 19 (ARPE-19) cells. Farrerol supplementation conspicuously reversed H2O2-related cell damage through declining the generation of intracellular reactive oxygen species (ROS) and MDA and increasing the concentrations of GSH and SOD. According to the results of the apoptosis assay, a farrerol pretreatment decreased the protein expression of the Bax/Bcl-2, cleaved caspase-3, PARP, caspase-8, and caspase-9 proteins. Furthermore, farrerol markedly activated Nrf2, thereby increasing the levels of antioxidant enzymes downstream of Nrf2, such as HO-1, NQO1, and GCLM. Knockdown of Nrf2 with a specific siRNA successfully suppressed farrerol-mediated HO-1 transcription and partially abolished the cytoprotective effect on ARPE-19 cells. Meanwhile, farrerol induced Akt and MAPK phosphorylation in a dose-related way. However, inhibiting Akt and MAPK substantially blocked the cytoprotective functions of farrerol. Therefore, farrerol enhanced Nrf2-mediated cytoprotection of oxidative damage caused by H2O2, which may be inseparable from the activation of Akt and MAPK.

show abstract

The pivotal role of nuclear factor erythroid 2-related factor 2 in diabetes-induced endothelial dysfunction

Cited by 45 publications

References 151 publications

Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells

Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells

Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging

Farrerol Enhances Nrf2‐Mediated Defense Mechanisms against Hydrogen Peroxide‐Induced Oxidative Damage in Human Retinal Pigment Epithelial Cells by Activating Akt and MAPK

Contact Info

Product

Resources

About