Role of redox-regulated transcription factors in inflammation, aging and age-related diseases

Lavrovsky, Yan; Chatterjee, Bandana; Clark, Robert A.; Roy, Arun K.

doi:10.1016/s0531-5565(00)00118-2

Cited by 275 publications

(165 citation statements)

References 53 publications

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“…However, beginning at Day 3, there was a consistent and significant stepwise increase in AP-1 binding activity, with maximal AP-1 binding activity occurring at Day 7 of elevated glucose culture. The mechanism by which ROS stimulates AP-1 binding activity is unknown; however, AP-1 is clearly activated by cellular oxidative stress [27]. Thus, we hypothesise that EC cultured in elevated glucose generate superoxide production over time (through mitochondrial respiration) that results in the activation of oxidative stress-related signalling pathways, including activation of the transcription factor AP-1.…”

Section: Discussionmentioning

confidence: 97%

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

et al. 2004

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Aims/hypothesis. Hyperglycaemia is a primary cause of vascular complications in diabetes. A hallmark of these vascular complications is endothelial cell dysfunction, which is partly due to the reduced production of nitric oxide. The aim of this study was to investigate the regulation of endothelial nitric oxide synthase (eNOS) activity by acute and chronic elevated glucose. Methods. Human aortic endothelial cells were cultured in 5.5 mmol/l (NG) or 25 mmol/l glucose (HG) for 4 h, 1 day, 3 days or 7 days. Mouse aortic endothelial cells were freshly isolated from C57BL/6J control and diabetic db/db mice. The expression and activity of eNOS were measured using quantitative PCR and nitrite measurements respectively. The binding of activator protein-1 (AP-1) to DNA in nuclear extracts was determined using electrophoretic mobility-shift assays. Results. Acute exposure (4 h) of human aortic endothelial cells to 25 mmol/l glucose moderately increased eNOS activity and eNOS mRNA and protein expression. In contrast, chronic exposure to elevated glucose (25 mmol/l for 7 days) reduced total nitrite levels (46% reduction), levels of eNOS mRNA (46% reduction) and eNOS protein (65% reduction). In addition, AP-1 DNA binding activity was increased in chronic HGcultured human aortic endothelial cells, and this effect was reduced by the specific inhibition of reactive oxygen species production through the mitochondrial electron transport chain. Mutation of AP-1 sites in the human eNOS promoter reversed the effects of HG. Compared with C57BL/6J control mice, eNOS mRNA levels in diabetic db/db mouse aortic endothelial cells were reduced by 60%. This decrease was reversed by the overexpression of manganese superoxide dismutase using an adenoviral construct. Conclusions/interpretation. In diabetes, the expression and activity of eNOS is regulated through glucosemediated mitochondrial production of reactive oxygen species and activation of the oxidative stress transcription factor AP-1. Abbreviations: AP-1, activator protein-1 · EC, endothelial cell · eNOS, endothelial nitric oxide synthase · FBS, fetal bovine serum · HG, high glucose · MnSOD, manganese superoxide dismutase · MOI, multiplicity of infection · NF-κB, nuclear factor-κB · NG, normal glucose · ROS, reactive oxygen species · UCP-1, uncoupling protein-1

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Section: Discussionmentioning

confidence: 97%

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

et al. 2004

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“…Interestingly, accumulation of very long chain fatty acids (VLC-fatty acids) due to impaired peroxisomal β-oxidation is reported to be associated with the induction of neuroinflammation/demyelination in human brain disease i.e., human Xadrenoleukodystrophy (X-ALD), hereditary peroxisomal disorder (Paintlia et al, 2003). Also, peroxisomal dysfunction has been linked with ROS generation in apoptosis (Baumgart et al, 2001), aging (Lavrovsky et al, 2000), and ischemia/reperfusion injury (Deplanque et al, 2003;Schrader and Fahimi, 2006) including pro-inflammatory disease processes (Poynter and Daynes, 1998). Peroxisomal dysfunctions manifested in inherited metabolic diseases due to one or more peroxisomal proteins deficiencies are thought to be responsible for ~ 18 unique fatal neurological disorders (Moser, 1996;Moser, 1999).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: Attenuation by N-acetyl cysteine

Paintlia

Contreras

et al. 2008

Experimental Neurology

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Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia (PVL) is the main substrate for cerebral palsy (CP) in premature infants. Previously, we reported that maternal LPS exposure causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by an antioxidant agent, N-acetyl cysteine (NAC). Herein, we elucidated the role of peroxisomes in LPS-induced neuroinflammation and cerebral white matter injury. Peroxisomes are important for detoxification of reactive oxidative species (ROS) and metabolism of myelin-lipids in OLs. Maternal LPS exposure induced selective depletion of developing OLs in the fetal brain which was associated with ROS generation, glutathione depletion and peroxisomal dysfunction. Likewise, hypomyelination in the postnatal brain was associated with decrease in peroxisomes in OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that proinflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-α agonist) reverses these effects of proinflammatory cytokines in the wild-type OLs, but not in PPAR-α (−/−) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-α siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-α (−/−) pregnant mice treated with NAC or WY14643 further suggested that PPAR-α activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and NACinduced protection is via a PPAR-α dependent mechanism expands therapeutic avenues for PVL and related demyelinating diseases.

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“…NF-B is a transcription factor which is known to play a pivotal role in mediating the gene expression of acute phase proteins such as C-reactive protein (CRP) or serum amyloid protein A (SAA), or a variety of inflammation/coagulation-related genes such as fibrinogen or plasminogen activator inhibitor-I (PAI-1) in the liver (Lavrovsky et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro

Iwasaki

Kambayashi

Asai

et al. 2007

Journal of Diabetes and its Complications

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Diabetes mellitus is frequently associated with coagulation disorders such as coronary heart disease or stroke. We aimed to clarify the molecular mechanism whereby hyperglycemia causes the procoagulant state. The HuH7 human hepatocyte cells were treated with high glucose alone, or in combination with proinflammatory cytokines, and the effects on the activity of the transcription factor NF-B, which mediates the expression of acute phase and coagulation-related genes, were examined. The results showed that increasing the medium glucose concentration from 3 to 24 mM significantly enhanced the NF-B-luciferase activity by 40% in the presence of insulin. The effect was promoter-specific, and was not mimicked by comparable hyperosmolality with L-glucose. Proinflammatory cytokines such as interleukin-1 and TNF-also stimulated NF-B-dependent transcription, and showed an additive effect with high glucose. Similar effects were obtained on acute phase or coagulation/fibrinolysis-related gene promoters such as fibrinogen or PAI-1, all of which are shown to have NF-B-mediated transcription. Finally, pretreatment of the cells with an antioxidant PDTC completely abolished the effect of high glucose, and markedly attenuated that of TNF-, suggesting the involvement of reactive oxygen species. These results suggest that 1) high glucose as well as proinflammatory cytokines have positive effects on NF-B-mediated transcription in an additive manner, and enhance coagulation-related gene expression, and 2) the effects are mediated, at least partly, by the generation of oxidative stress, and may be responsible for the high prevalence of thrombotic disorders in the metabolic syndrome with diabetes, hyperinsulinemia, obesity and/or inflammation.

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Role of redox-regulated transcription factors in inflammation, aging and age-related diseases

Cited by 275 publications

References 53 publications

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: Attenuation by N-acetyl cysteine

High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro

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