Regulation of protein kinase C by nitroarachidonic acid: Impact on human platelet activation

Bonilla, Lucía; O'Donnell, Valerie Bridget; Clark, Stephen P.; Rubbo, Homero; Trostchansky, Andrés

doi:10.1016/j.abb.2013.03.001

Cited by 24 publications

(13 citation statements)

References 46 publications

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“…Although F 4 -neuroprostanes derived from Dha, like Aa derived F 2 -isoprostanes, have been related to various cardiovascular and neurodegenerative disorders [45,46], here we can only speculate about the beneficial effects of Dha-derived nitration products, as was shown for AaNO 2 [27,31,32] and all other singly nitrated fatty acids. Lipid peroxidation products usually posses proinflammatory properties [47]; however current data on biological activities of NO 2 -FA support their anti-inflammatory effects via both cGMPdependent and cGMP-independent mechanisms.…”

Section: No 2 -Fa In the Cardiomyocyte Nitrosative Stress Modelmentioning

confidence: 88%

“…Lipid peroxidation products usually posses proinflammatory properties [47]; however current data on biological activities of NO 2 -FA support their anti-inflammatory effects via both cGMPdependent and cGMP-independent mechanisms. Although the overproduction of NO 2 -FA was observed during inflammation, a series of anti-inflammatory effects were reported for LaNO 2 [48][49][50] , OaNO 2 [15,24], and AaNO 2 [27,31,32]. The question about biological activities of multiply nitrated and nitro-oxidized PUFA remains open owing to the lack of the data on their biological availability.…”

Section: No 2 -Fa In the Cardiomyocyte Nitrosative Stress Modelmentioning

confidence: 97%

“…Release of nitric oxide by AaNO 2 can induce cyclic GMP (cGMP)-dependent vasorelaxation and downregulate inducible nitric oxide synthase [31]. Additionally, AaNO 2 was shown to prevent NADPH oxidase assembly [27], regulate protein kinase C [32], and inhibit oxygenase activities of PGHS-1 and PGHS-2.…”

Section: Introductionmentioning

confidence: 96%

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Profiling and relative quantification of multiply nitrated and oxidized fatty acids

et al. 2015

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The levels of nitro fatty acids (NO2-FA), such as nitroarachidonic, nitrolinoleic, nitrooleic, and dinitrooleic acids, are elevated under various inflammatory conditions, and this results in different anti-inflammatory effects. However, other multiply nitrated and nitro-oxidized FAs have not been studied so far. Owing to the low concentrations in vivo, NO2-FA analytics usually relies on targeted gas chromatography-tandem mass spectrometry (MS/MS) or liquid chromatography-MS/MS, and thus require standard compounds for method development. To overcome this limitation and increase the number and diversity of analytes, we performed in-depth mass spectrometry (MS) profiling of nitration products formed in vitro by incubating fatty acids with NO2BF4, and ONOO(-). The modified fatty acids were used to develop a highly specific and sensitive multiple reaction monitoring LC-MS method for relative quantification of 42 different nitrated and oxidized species representing three different groups: singly nitrated, multiply nitrated, and nitro-oxidized fatty acids. The method was validated in in vitro nitration kinetic studies and in a cellular model of nitrosative stress. NO2-FA were quantified in lipid extracts from 3-morpholinosydnonimine-treated rat primary cardiomyocytes after 15, 30, and 70 min from stress onset. The relatively high levels of dinitrooleic, nitroarachidonic, hydroxynitrodocosapenataenoic, nitrodocosahexaenoic, hydroxynitrodocosahexaenoic, and dinitrodocosahexaenoic acids confirm the presence of multiply nitrated and nitro-oxidized fatty acids in biological systems for the first time. Thus, in vitro nitration was successfully used to establish a targeted LC-MS/MS method that was applied to complex biological samples for quantifying diverse NO2-FA. Graphical Abstract Schematic representation of study design which combined in vitro nitration of different fatty acids, MS/MS characterization and optimization of MRM method for relative quantification, which was applied to follow dynamic of fatty acid nitration in cellular model of SIN-1 treated cardiomyoctes.

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Section: No 2 -Fa In the Cardiomyocyte Nitrosative Stress Modelmentioning

confidence: 88%

Section: No 2 -Fa In the Cardiomyocyte Nitrosative Stress Modelmentioning

confidence: 97%

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Profiling and relative quantification of multiply nitrated and oxidized fatty acids

et al. 2015

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“…Herein, the inhibition of platelet activation occurred in whole blood for 6 hr following 15 NO 2 − dosing, with the inhibition of platelet activation still evident well beyond the physiologic plasma NO 2 − peak and the time of 15 NO-Hb detection. Previous in vitro studies revealed that two synthetic nitro-fatty acids, nitro-linoleic acid and nitro-arachidonic acid (at high concentrations in buffered saline), inhibited platelet aggregation and activation, respectively 79, 80 . In the more clinically-relevant study herein, 15 NO 2 − administration in vivo decreased platelet activation in whole blood at 6 hr.…”

Section: Discussionmentioning

confidence: 99%

Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate

et al. 2017

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Dietary nitrate (NO3−) and nitrite (NO2−) support nitric oxide (·NO) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins and unsaturated fatty acids. To explore the kinetics of NO3− and NO2− metabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes Na15NO3 and Na15NO2 were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of 15NO2− to 15NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting 15NO-deoxyhemoglobin complexes. This formation of 15NO also translated to decreased systolic and mean arterial blood pressures and inhibition of platelet function. Upon concurrent administration of cLA, there was a significant increase in plasma cLA nitration products 9- and 12-15NO2-cLA. Co-administration of cLA with 15NO2− also impacted the pharmacokinetics and physiological effects of 15NO2−, with cLA administration suppressing plasma NO3− and NO2− levels, decreasing 15NO-deoxyhemoglobin formation, NO2− inhibition of platelet activation, and the vasodilatory actions of NO2−, while enhancing the formation of 9- and 12-15NO2-cLA. These results indicate that the biochemical reactions and physiologic responses to oral 15NO3− and 15NO2− are significantly impacted by dietary constituents such as unsaturated lipids. This can explain the variable responses to NO3− and NO2− supplementation in clinical trials and reveals dietary strategies for promoting the generation of pleiotropic nitrogen oxide-derived lipid signaling mediators.

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“…These anti-platelet effects were cGMP-independent and did not involve Ca 2+ -store-dependent mobilization, providing a possible novel mechanism for platelet regulation in vivo . Signaling downstream of protein kinase C (PKC), such as α-granule secretion and extracellular signal-regulated kinase 2 activation, was strongly inhibited by NO 2 -AA (42). Inhibition of PKCα translocation to the plasma membrane represents a potential mechanism for platelet regulation in vivo .…”

Section: Nitroalkene Activation Of Anti-inflammatory Signaling Pathwaysmentioning

confidence: 99%

Nitro-fatty acids: novel anti-inflammatory lipid mediators

Rubbo

2013

Braz J Med Biol Res

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Nitro-fatty acids are formed and detected in human plasma, cell membranes, and tissue, modulating metabolic as well as inflammatory signaling pathways. Here we discuss the mechanisms of nitro-fatty acid formation as well as their key chemical and biochemical properties. The electrophilic properties of nitro-fatty acids to activate anti-inflammatory signaling pathways are discussed in detail. A critical issue is the influence of nitroarachidonic acid on prostaglandin endoperoxide H synthases, redirecting arachidonic acid metabolism and signaling. We also analyze in vivo data supporting nitro-fatty acids as promising pharmacological tools to prevent inflammatory diseases.

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Regulation of protein kinase C by nitroarachidonic acid: Impact on human platelet activation

Cited by 24 publications

References 46 publications

Profiling and relative quantification of multiply nitrated and oxidized fatty acids

Profiling and relative quantification of multiply nitrated and oxidized fatty acids

Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate

Nitro-fatty acids: novel anti-inflammatory lipid mediators

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