Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

Lu, Haocheng; Sun, Jin; Liang, Wenying; Zhang, Jifeng; Rom, Oren; Garcia-Barrio, Minerva T.; Li, Shengdi; Villacorta, Luis; Schöpfer, Francisco J.; Freeman, Bruce Α.; Chen, Y. Eugene; Fan, Yanbo

doi:10.1152/physiolgenomics.00127.2018

Cited by 16 publications

(13 citation statements)

References 71 publications

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“…Among NO 2 -FA, NO 2 -CLA induced a greater magnitude of PPARγ activation, as shown by its unique upregulation of CD36 expression, a response inhibited by GW9662. This expands our knowledge of the biological actions of NO 2 -CLA in monocytes and macrophages and presumably other cells [5,17,73,74]. Because CLA behaves as a preferential FA target for nitration at physiological conditions [5], PPARγ activation by NO 2 -CLA could be biologically more relevant than that mediated by other NO 2 -FA.…”

Section: Discussionmentioning

confidence: 96%

A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes

Bervejillo

Bonanata²,

Franchini

et al. 2020

Redox Biology

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Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPARγ), which is predominantly expressed in adipocytes and myeloid cells. Herein, we explored molecular and cellular events associated with PPARγ activation by NO2-FA in monocytes and macrophages. NO2-FA induced the expression of two PPARγ reporter genes, Fatty Acid Binding Protein 4 (FABP4) and the scavenger receptor CD36, at early stages of monocyte differentiation into macrophages. These responses were inhibited by the specific PPARγ inhibitor GW9662. Attenuated NO2-FA effects on PPARγ signaling were observed once cells were differentiated into macrophages, with a significant but lower FABP4 upregulation, and no induction of CD36. Using in vitro and in silico approaches, we demonstrated that NO2-FA bind to FABP4. Furthermore, the inhibition of monocyte FA binding by FABP4 diminished NO2-FA-induced upregulation of reporter genes that are transcriptionally regulated by PPARγ, Keap1/Nrf2 and HSF1, indicating that FABP4 inhibition mitigates NO2-FA signaling actions. Overall, our results affirm that NO2-FA activate PPARγ in monocytes and upregulate FABP4 expression, thus promoting a positive amplification loop for the downstream signaling actions of this mediator.

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Section: Discussionmentioning

confidence: 96%

A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes

Bervejillo

Bonanata²,

Franchini

et al. 2020

Redox Biology

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“…At this point, we hypothesized that nitrofatty acids (NO 2 -FAs) could be responsible for the post-translational modification of Tsa1 because these new signaling molecules have been related to the activation of the HSR and the chaperone network [25,26,46], which suggests a key role for these molecules in the heat stress response. NO 2 -FAs are pleiotropic signaling molecules that trigger a powerful antioxidant response.…”

Section: Discussionmentioning

confidence: 99%

Nitro-Oleic Acid-Mediated Nitroalkylation Modulates the Antioxidant Function of Cytosolic Peroxiredoxin Tsa1 during Heat Stress in Saccharomyces cerevisiae

et al. 2022

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Heat stress is one of the abiotic stresses that leads to oxidative stress. To protect themselves, yeast cells activate the antioxidant response, in which cytosolic peroxiredoxin Tsa1 plays an important role in hydrogen peroxide removal. Concomitantly, the activation of the heat shock response (HSR) is also triggered. Nitro-fatty acids are signaling molecules generated by the interaction of reactive nitrogen species with unsaturated fatty acids. These molecules have been detected in animals and plants. They exert their signaling function mainly through a post-translational modification called nitroalkylation. In addition, these molecules are closely related to the induction of the HSR. In this work, the endogenous presence of nitro-oleic acid (NO2-OA) in Saccharomyces cerevisiae is identified for the first time by LC-MS/MS. Both hydrogen peroxide levels and Tsa1 activity increased after heat stress with no change in protein content. The nitroalkylation of recombinant Tsa1 with NO2-OA was also observed. It is important to point out that cysteine 47 (peroxidatic) and cysteine 171 (resolving) are the main residues responsible for protein activity. Moreover, the in vivo nitroalkylation of Tsa1 peroxidatic cysteine disappeared during heat stress as the hydrogen peroxide generated in this situation caused the rupture of the NO2-OA binding to the protein and, thus, restored Tsa1 activity. Finally, the amino acid targets susceptible to nitroalkylation and the modulatory effect of this PTM on the enzymatic activity of Tsa1 are also shown in vitro and in vivo. This mechanism of response was faster than that involving the induction of genes and the synthesis of new proteins and could be considered as a key element in the fine-tuning regulation of defence mechanisms against oxidative stress in yeast.

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“…A total of 266 million reads were generated, with an average of 38 million reads per sample. RNA-Seq read mapping was performed as described previously ( 59 ). In brief, FastQC (Babraham Bioinformatics) was used for quality control of the sequencing reads from each sample.…”

Section: Methodsmentioning

confidence: 99%

BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis

Zhao¹,

Zhao²,

Lu³

et al. 2022

Journal of Clinical Investigation

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Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis; yet, little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMC), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both AngII-and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMC resulted in the loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex, suppressed VSMC inflammation by promoting a repressive chromatin state of the NFκB-target genes, as well as prevented VSMC apoptosis through transcriptional activation of KLF5-dependent BCL2 expression. Together, our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA.

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Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

Cited by 16 publications

References 71 publications

A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes

A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes

Nitro-Oleic Acid-Mediated Nitroalkylation Modulates the Antioxidant Function of Cytosolic Peroxiredoxin Tsa1 during Heat Stress in Saccharomyces cerevisiae

BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis

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