Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts

Villacorta, Luis; Chang, Lin; Salvatore, Sonia R.; Ichikawa, Tomonaga; Zhang, Jifeng; Petrovic-Djergovic, Danica; Lu, Jianyi; Carlsen, Harald; Schöpfer, Francisco J.; Freeman, Bruce Α.; Chen, Y. Eugene

doi:10.1093/cvr/cvt002

Cited by 103 publications

(101 citation statements)

References 51 publications

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“…Recent reports indicate that NO 2 -OA promotes beneficial metabolic and anti-inflammatory responses by modulating Nrf2-dependent antioxidant gene expression, sEH activity, and TLR4/NFkB signaling (6)(7)(8). The administration of pure synthetic NO 2 -OA induces beneficial signaling actions and physiological responses in animal models of metabolic, vascular, renal, and pulmonary disease (12).…”

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

confidence: 99%

“…The electrophilic nature of nitro-alkenes undergoes: 1) reversible Michael DISCUSSION Nitration of unsaturated FAs and the corresponding generation of electrophilic NO 2 -FA occur during acidic conditions of digestion and oxidative inflammatory conditions (3,4,17,18,35). 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).…”

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

confidence: 99%

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

confidence: 99%

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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“…These NO 2 and N 2 O 3 -generating reactions are also likely to produce nitro-fatty acids (14,154,193,194) in the RBC membrane. Nitro-fatty acid derivatives of oleic acid have been found in RBC membranes (15).…”

Section: Preserving Transporting and Delivering Hb-derived Nox Bioamentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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“…Nitration of OLA is mediated by peroxynitrite, acidified nitrite, and myeloperoxidase in the presence of hydrogen peroxide and nitrite [21]. Characterization of the biological functions of nitrofatty acids has revealed clinically relevant protection from inflammatory injury in a number of cardiovascular and metabolic experimental models, including atherosclerosis [22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Nitro‐Oleic Acid Reduces J774A.1 Macrophage Oxidative Status and Triglyceride Mass: Involvement of Paraoxonase2 and Triglyceride Metabolizing Enzymes

Rom

Volkova

Aviram

2016

Lipids

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Nitro-fatty acids possess anti-atherogenic properties, but their effects on macrophage oxidative status and lipid metabolism that play important roles in atherosclerosis development are unclear. This study compared the effects of nitro-oleic acid (OLA-NO2) with those of native oleic acid (OLA) on intracellular reactive oxygen species (ROS) generation, anti-oxidants and metabolism of triglycerides and cholesterol in J774A.1 macrophages. Upon incubating the cells with physiological concentrations of OLA-NO2 (0-1 µM) or with equivalent levels of OLA, ROS levels measured by 2, 7-dichlorofluorescein diacetate, decreased dose-dependently, but the anti-oxidative effects of OLA-NO2 were significantly augmented. Copper ion addition increased ROS generation in OLA treated macrophages without affecting OLA-NO2 treated cells. These effects could be attributed to elevated glutathione levels and to increased activity and expression of paraoxonase2 that were observed in OLA-NO2 vs OLA treated cells. Beneficial effects on triglyceride metabolism were noted in OLA-NO2 vs OLA treated macrophages in which cellular triglycerides were reduced due to attenuated biosynthesis and accelerated hydrolysis of triglycerides. Accordingly, OLA-NO2 treated cells demonstrated down-regulation of diacylglycerol acyltransferase1, the key enzyme in triglyceride biosynthesis, and increased expression of hormone-sensitive lipase and adipose triglyceride lipase that regulate triglyceride hydrolysis. Finally, OLA-NO2 vs OLA treatment resulted in modest but significant beneficial effects on macrophage cholesterol metabolism, reducing cholesterol biosynthesis rate and low density lipoprotein influx into the cells, while increasing high density lipoprotein-mediated cholesterol efflux from the macrophages. Collectively, compared with OLA, OLA-NO2 modestly but significantly reduces macrophage oxidative status and cellular triglyceride content via modulation of cellular anti-oxidants and triglyceride metabolizing enzymes.

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Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts

Cited by 103 publications

References 51 publications

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Nitro‐Oleic Acid Reduces J774A.1 Macrophage Oxidative Status and Triglyceride Mass: Involvement of Paraoxonase2 and Triglyceride Metabolizing Enzymes

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