Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation

Rudolph, Tanja K.; Ravekes, Thorben; Klinke, Anna; Friedrichs, Kai; Mollenhauer, Martin; Pekarová, Michaela; Ambrožová, Gabriela; Martišková, Hana; Kaur, Jatinderjit; Matthes, Bianca; Schwoerer, Alexander Peter; Woodcock, Steven R.; Kubala, Lukáš; Freeman, Bruce Α.; Baldus, Stephan; Rudolph, Volker

doi:10.1093/cvr/cvv254

Cited by 40 publications

(38 citation statements)

References 34 publications

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“…Together with the observation that TGF-β did not activate STAT, MAPK, or NF-κB signaling, we postulate that Smad activation represents one of the key events where OA-NO 2 modulates signaling events leading to EndMT. These results, confirmed also in HUVECs, are in agreement with previous observations of the involvement of Smad proteins in the regulation of fibrosis [2, 25]. Nevertheless, this does not exclude the involvement of other signaling molecules or pathways in the inception of fibrotic processes and the actions of OA-NO 2 .…”

Section: Discussionsupporting

confidence: 91%

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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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Section: Discussionsupporting

confidence: 91%

“…Placing special focus on the modulation of macrophage functions [2, 25] we now elucidate the effects of nitro-oleic acid (OA-NO 2 ) on inflammation and the EndMT responses of ECs. We hypothesize that OA-NO 2 inhibits pathological tissue remodeling induced by the activation of macrophages and ECs during chronic inflammation.…”

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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“…M-CSFR levels were upregulated in both CSF-differentiated BMMs and reduced by NO 2 -OA treatment. These results are consistent with our previous findings that NO 2 -OA (i) reduces the macrophage numbers detected in lung tissue of mice with hypoxia-induced pulmonary hypertension [34], (ii) partially prevents the M1 macrophage accumulation in fibrotic atrium of angiotensin II-treated mice [35], and (iii) downregulates monocyte/macrophage accumulation in atherosclerotic plaques in a murine model of atherosclerosis [36]. Since these pathologies are also linked with increased levels of M-CSF and GM-CSF [13–18], we suggest that NO 2 -FA-mediated reduction of macrophage infiltration is a consequence of the inhibition of macrophage differentiation and proliferation.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, NO 2 -OA reduces the total numbers of macrophages accumulated in different types of an inflamed tissues – including atherosclerotic plaques [36], lung tissue [34], and heart atrium [35], affirming the potential of NO 2 -FA as mediators that can regulate diverse macrophage functions. Herein, we reveal that NO 2 -OA also influences also the process of M-CSF- and GM-CSF-induced macrophage differentiation, which could represent another crucial finding for successful realization of clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Verescakova

Ambrožová

Kubala

et al. 2017

Free Radical Biology and Medicine

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Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1–5 min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

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“…The electrophilic properties of NO 2 -FA induce anti-inflammatory and cytoprotective actions via reversible posttranslational modification of transcriptional regulatory proteins, such as NF-kB, Keap1/ Nrf2, and PPAR-, and enzymes such as xanthine oxidoreductase and sEH (6)(7)(8)(36)(37)(38). Beneficial metabolic and anti-inflammatory effects of NO 2 -FAs have been shown in animal models of fibrosis, atherosclerosis, renal and cardiac ischemia reperfusion, restenosis, and diabetes (12,(39)(40)(41)(42)(43)(44). in nitro-alkane metabolites could reflect their cellular reuptake and esterification into complex lipids.…”

Section: No 2 -Oa Esterification and Metabolism In Adipose Tissue In mentioning

confidence: 99%

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Fazzari

Khoo

Woodcock

et al. 2017

Journal of Lipid Research

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inflammatory and metabolic stress (1-3). In particular, the reaction between unsaturated FAs and the nitric oxide and nitrite (NO 2  )-derived radical species nitrogen dioxide (·NO 2 ) generates electrophilic FA nitro-alkene byproducts (NO 2 -FAs) (4). These molecules are endogenously detected and have been observed to mediate salutary responses in models of inflammatory injury and oxidative stress. Current data supports that NO 2 -FAs predominantly signal via posttranslational protein modifications, specifically of functionally significant Cys residues of nuclear transcription factor erythroid 2-related factor 2 (Nrf2), soluble epoxide hydrolase (sEH), p65 subunit of nuclear factor kappa B (NF-kB), transient receptor potential cation channel subfamily V member 1 (TRPV1), and heat shock factor-1 (HSF-1) (5-9).NO 2 -FAs have been detected in a variety of species, including mammals and plants, as both free acid and as complex lipid-esterified species (3, 10, 11). For example, NO 2 -FAs are detected at micromolar concentrations in rodent cardiac mitochondria subjected to an episode of ischemia-reperfusion and at nanomolar concentrations in healthy human plasma and urine (12)(13)(14). Additionally, [D 4 ]octadecenoic acid; Nrf2, nuclear transcription factor erythroid 2-related factor 2; OA, oleic acid; PC, phosphatidylcholine; QWBA, quantitative whole-body autoradiography; sEH, soluble epoxide hydrolase; TAG, triacylglyceride. The designations "9-NO 2 -" and "10-NO 2 -"OA are used herein to describe the position of the nitro group in the fatty acid chain and do not refer to IUPAC nomenclature. MED Foundation (M.F.), National Institutes of Health Grants R01-AT006822 (F.J.S.), R01-HL64937, R01-HL132550, and P01-HL103455 (B.A.F.), and American Heart Association Grant 14GRNT20170024 (F.J.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the1 To whom correspondence should be addressed. e-mail: freerad@pitt.edu (B.A.F.); fjs2@pitt.edu (F.J.S.) The online version of this article (available at http://www.jlr.org) contains a supplement.

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Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation

Abstract: OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs.

Cited by 40 publications

References 34 publications

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

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

Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

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