Nitrooleate Mediates Nitric Oxide Synthase Activation in Endothelial Cells

Shin, Eunju; Yeo, Eun-Ju; Lim, Jihye; Chang, Yun Hee; Park, Haeryun; Shim, Eugene; Chung, Haeyon; Hwang, Hye Jin; Chun, Jiyeon; Hwang, Jae Ryoung

doi:10.1007/s11745-014-3893-8

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…The replacement of HSP90 with its associated proteins can be critical to the regulation of those proteins, as demonstrated in studies that showing that nitrated lipid, OLA-NO 2 , enhances eNOS/Hsp90 interaction by replacing the eNOS/cav1 interaction, resulting in increasing eNOS activity [ 42 ]. We sought to determine whether an Aβ-induced augmentation of eNOS/HSP90 had an effect on Akt/HSP90.…”

Section: Resultsmentioning

confidence: 99%

Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Lamoke

Mazzone

Persichini

et al. 2015

J Neuroinflammation

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BackgroundAmyloid β (Aβ)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer’s disease (AD). Aβ is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO).MethodIn this study, we investigated Aβ-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process.ResultsTreatments of endothelial cells (EC) with Aβ promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Aβ stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Aβ effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation.ConclusionsThe obtained data support the hypothesis that oxidative damage caused by Aβ results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Aβ-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients.

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Section: Resultsmentioning

confidence: 99%

Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Lamoke

Mazzone

Persichini

et al. 2015

J Neuroinflammation

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“…This latter mechanism can serve as an adaptive response to oxidative stress, since the physiological concentrations (~1 μM) that are generated clinically [20-22] are sufficient to mediate pleiotropic signaling responses that promote the resolution of inflammation [23]. Recent evidence suggests that these pluripotent signaling mediators can, as a consequence of post-translational protein modification, regulate many physiological and pathological processes by affecting a whole range of mammalian cell functions (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence suggests that these pluripotent signaling mediators can, as a consequence of post-translational protein modification, regulate many physiological and pathological processes by affecting a whole range of mammalian cell functions (e.g. the activation of macrophages and neutrophils, vasorelaxation, angiogenesis and platelet aggregation) [2, 3, 22, 24]. …”

Section: Introductionmentioning

confidence: 99%

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition

Ambrožová

Fidlerova

Verescakova

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. Methods The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. Results OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. Conclusions The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. General significance These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

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“…In line with the activation by Src was the increased phosphorylation of eNOS at the stimulating site Ser1177 in response to oxidative stress [ 31 ] implicated in anthrax pathology [ 32 ]. However, the inhibiting site Ser113 [ 33 ] also displayed an increased phosphorylation thus precluding a conclusion on the functional status of this enzyme.…”

Section: Resultsmentioning

confidence: 99%

Reverse-Phase Microarray Analysis Reveals Novel Targets in Lymph Nodes of Bacillus anthracis Spore-Challenged Mice

et al. 2015

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Anthrax is a frequently fatal infection of many animal species and men. The causative agent Bacillus anthracis propagates through the lymphatic system of the infected host; however, the specific interactions of the host and microbe within the lymphatics are incompletely understood. We report the first description of the phosphoprotein signaling in the lymph nodes of DBA/2 mice using a novel technique combining the reverse-phase microarray with the laser capture microdissesction. Mice were challenged into foot pads with spores of toxinogenic, unencapsulated Sterne strain. The spores quickly migrated to the regional popliteal lymph nodes and spread to the bloodstream as early as 3 h post challenge. All mice died before 72 h post challenge from the systemic disease accompanied by a widespread LN tissue damage by bacteria, including the hemorrhagic necrotizing lymphadenitis, infiltration of CD11b+ and CD3+ cells, and massive proliferation of bacteria in lymph nodes. A macrophage scavenger receptor CD68/macrosialin was upregulated and found in association with vegetative bacteria likely as a marker of their prior interaction with macrophages. The major signaling findings among the 65 tested proteins included the reduced MAPK signaling, upregulation of STAT transcriptional factors, and altered abundance of a number of pro- and anti-apoptotic proteins with signaling properties opposing each other. Downregulation of ERK1/2 was associated with the response of CD11b+ macrophages/dendritic cells, while upregulation of the pro-apoptotic Puma indicated a targeting of CD3+ T-cells. A robust upregulation of the anti-apoptotic survivin was unexpected because generally it is not observed in adult tissues. Taken together with the activation of STATs it may reflect a new pathogenic mechanism aimed to delay the onset of apoptosis. Our data emphasize a notion that the net biological outcome of disease is determined by a cumulative impact of factors representing the microbial insult and the protective capacity of the host.

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Nitrooleate Mediates Nitric Oxide Synthase Activation in Endothelial Cells

Cited by 8 publications

References 32 publications

Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition

Reverse-Phase Microarray Analysis Reveals Novel Targets in Lymph Nodes of Bacillus anthracis Spore-Challenged Mice

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