Nuclear Factor (Erythroid-Derived 2)-Like 2 and Thioredoxin-1 in Atherosclerosis and Ischemia/Reperfusion Injury in the Heart

Jakobs, Philipp; Serbulea, Vlad; Leitinger, Norbert; Eckers, Anna; Haendeler, Judith

doi:10.1089/ars.2016.6795

Cited by 56 publications

(41 citation statements)

References 117 publications

(108 reference statements)

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“…The observed increase in the NQO1 gene expression in our study might be a response to NRF2-stimulating conditions prevalent in patients with CKD, like oxidative stress or lipopolysaccharide-induced inflammation [25, 26]. Patients with coexisting CVD, which is also associated with oxidative stress, might be especially affected [27]. This is supported by the higher CVD prevalence in CKD 1–5 patients with a higher NQO1 gene expression that we observed.…”

Section: Discussionsupporting

confidence: 72%

“…Therefore, as the systemic application of NRF2 activators affects different cell and tissue types, the NRF2 pathway in kidney disease needs to be investigated in different human cells and tissues. This is of relevance as the overactivation of a potent transcription factor like NRF2 was suggested as potentially deleterious for the cardiovascular system [27]. Therefore, a preexisting activation of the NRF2 system in CKD patients especially with CVD, as suggested by our results, could be seen in line with the increased rate of cardiovascular events in the BEACON trial [11].…”

Section: Discussionsupporting

confidence: 67%

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Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

Shen

Rasmussen

Dong

et al. 2017

Oxidative Medicine and Cellular Longevity

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Reduced nuclear factor erythroid 2-related factor 2 (NRF2) pathway activity was reported in models of chronic kidney disease (CKD). Pharmacological activation of NRF2 is supposed to improve renal function, but data concerning the NRF2 activity in human CKD are lacking. We investigated the NRF2 target NAD(P)H:quinone oxidoreductase 1 (NQO1) as a readout parameter for NRF2 activity in monocytes of CKD patients (n = 63) compared to those of healthy controls (n = 16). The NQO1 gene expression was quantified using real-time PCR and the protein content by in-cell Western assays. We found a 3-4-fold increase in NQO1 gene expression in CKD 1–5 (n = 29; 3.5 for NQO1/ribosomal protein L41; p < 0.001). This was accompanied by a 1.1-fold increase in NQO1 protein (p = 0.06). Cardiovascular disease prevalence was higher in CKD 1–5 patients with higher compared to those with lower NQO1 gene expression (p = 0.02). In advanced uremia, in dialysis patients (n = 34), NQO1 gene expression was less robustly upregulated than that in CKD 1–5, while NQO1 protein was not upregulated. We conclude that in mononuclear cells of CKD patients, the NRF2 pathway is activated by coexisting pathogenic mechanisms, but in advanced uremia, the effectiveness of this upregulation is reduced. Both processes could interfere with pharmacological NRF2 activation.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 67%

Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

Shen

Rasmussen

Dong

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…In MIRI, Nrf2 downregulates the inflammatory factor myeloperoxidase (MPO) and simultaneously upregulates the levels of antioxidants, such as SOD and glutathione peroxidase (GPx), to counter inflammation and oxidative stress. Jakobs et al demonstrated that Nrf2 is maintained in the reduced state to increase the expression of antioxidative enzymes by thioredoxin-1 (Trx-1), and in turn, Nrf2 regulates the activation of Trx-1 through two AREs [45]. As demonstrated by Chen et al, Nrf2 is able to not only function after inflammation and oxidative stress but also after reperfusion injury, via activation by trigger factors such as emulsified isoflurane (EI) [46].…”

Section: Myocardial Ischemia Reperfusion Injury (Miri)mentioning

confidence: 99%

“…Regulates the activation of thioredoxin-1 (Trx-1) through two antioxidant response elements [45] Regulates ROS levels [46] Atherosclerosis (AS)…”

Section: Viral Myocarditismentioning

confidence: 99%

The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases

Zhang

Lei

et al. 2020

Cardiology Research and Practice

109

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Cardiovascular disease, which can lead to angina and shortness of breath, remains one of the most serious threats to human health. Owing to its imperceptible symptoms, it is difficult to determine the pathogenesis and treatment methods for cardiovascular disease. Nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) is a protein found in all cells of the human body. It is activated, transferred to the nucleus, and bound to DNA by antioxidant response elements (AREs). As a regulator of the antioxidant system, it upregulates the expression of HO-1 to reduce oxidative stress. Nrf2/HO-1 also has the ability to modulate calcium levels to prevent ferroptosis, pyroptosis, autophagy, programmed cell necrosis, alkaliptosis, and clockophagy. In view of the importance of Nrf2/HO-1 in the regulation of homeostasis, this review summarizes current research on the relationship between cardiovascular disease and Nrf2/HO-1. Normal cardiovascular diseases, such as viral myocarditis and myocardial ischemia-reperfusion injury, have been treated with Nrf2/HO-1. Rheumatic heart disease, cardiac tumors, arteriosclerosis, arrhythmia, hypertensive heart disease, and myocardial infarction have also been treated during experiments. Research has demonstrated the clinical application of Nrf2/HO-1 in pediatric cardiovascular disease; further clinical trials will help elucidate the potential of the Nrf2/HO-1 signaling axis.

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“…Besides the proteins involved in the lipid metabolism (apolipoproteins and their receptors, PCSK9, paraoxonases, etc. ), several main classes of biomolecules also play an important role in the pathogenesis of atheroma formation: scavenger receptors [3][4][5][6]; growth factors and other cytokines and chemokines [7][8][9][10][11][12][13][14]; adhesive moleculesintegrins, cadherins, selectins and immunoglobulins [15][16][17][18]; matrix metalloproteinases [19][20][21]; nitric oxide (NO) and endothelial NO synthase [22][23][24]; free radicals, oxidative stress and antioxidant systems [23][24][25][26][27]; transcription factors [28][29][30][31]. Atherogenesis is a complex process driven by interactions between environmental and genetic factors and their discovery and validation in individuals with different population background could impact on the prevention and risk estimation of CHD.…”

Section: Introductionmentioning

confidence: 99%

Prioritization of genetic variants predisposing to coronary heart disease in the Bulgarian population using centenarian exomes

Ganev

Balabanski

Serbezov

et al. 2019

Biotechnology & Biotechnological Equipment

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Coronary heart disease (CHD) is a major cause of mortality and morbidity in Europe. CHD is usually caused by atherosclerosis. Despite extensive studies that have identified a large number of genetic variants, strong evidence of association with CHD are not easily replicable in different populations. Two DNA pools were constructed: one with 32 Bulgarian centenarians and one with 61 young healthy Bulgarian individuals. The pools were whole-exome sequenced and variants were annotated and quality filtered (89,810 filtered variants). Allele frequencies were estimated and Fisher's exact test was used to evaluate the significance of allele frequency differences between the two pools. Two publicly available databases, Ensembl and DisGeNET, were used as a source of 2025 CHD-associated variants (CHD-AVs). These single nucleotide polymorphisms were screened in our data and 158 variants in 133 genes were found. ToppGene pathways analysis of genes called in both pools discovered participation of 37 genes in 9 significantly overrepresented pathways. Eight variants in these 37 genes have significantly higher frequency in young individuals, and are nominated for CHD association. Variants called only in the young individuals pool (13 variants) are also nominated for association with CHD. Based on sufficiently unambiguous literature data, from the nominated variants, we prioritize five as associated with CHD in the studied Bulgarian sample. Centenarian genomes can be used to provide additional information regarding the clinical relevance of genetic variants reported as associated with CHD.

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Nuclear Factor (Erythroid-Derived 2)-Like 2 and Thioredoxin-1 in Atherosclerosis and Ischemia/Reperfusion Injury in the Heart

Abstract: Therefore, the length of treatment with Nrf2 activators and/or Trx-1 has first to be studied in more detail in cardiovascular disorders. Moreover, a combination of Nrf2 activators and Trx-1 should be investigated and taken into consideration. Antioxid. Redox Signal. 26, 630-644.

Cited by 56 publications

References 117 publications

Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases

Prioritization of genetic variants predisposing to coronary heart disease in the Bulgarian population using centenarian exomes

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