Evaluation of nitroalkenes as nitric oxide donors

Gorczynski, Michael J.; Huang, Jinming; Lee, Heather; King, S. Bruce

doi:10.1016/j.bmcl.2007.01.016

Cited by 40 publications

(24 citation statements)

References 30 publications

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“…Nitrated fatty acids have been shown to be stable in lipophilic environments, but they have been shown to release NO in aqueous solutions . However, compared with other nitrated fatty acids, OA-NO 2 is relatively stable (half-life aq of approximately 2 h) (Gorczynski et al, 2007), and so it was not surprising that the NO scavenger carboxy-PTIO had no effect on 9-OA-NO 2 TRPA1 activation. The capacity of NO itself to activate TRPA1 is not yet clear.…”

Section: Discussionmentioning

confidence: 99%

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Nitrooleic Acid, an Endogenous Product of Nitrative Stress, Activates Nociceptive Sensory Nerves via the Direct Activation of TRPA1

Taylor‐Clark

Ghatta

Bettner³

et al. 2009

Mol Pharmacol

166

136

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Transient Receptor Potential A1 (TRPA1) is a nonselective cation channel, preferentially expressed on a subset of nociceptive sensory neurons, that is activated by a variety of reactive irritants via the covalent modification of cysteine residues. Excessive nitric oxide during inflammation (nitrative stress), leads to the nitration of phospholipids, resulting in the formation of highly reactive cysteine modifying agents, such as nitrooleic acid (9-OA-NO 2 ). Using calcium imaging and electrophysiology, we have shown that 9-OA-NO 2 activates human TRPA1 channels (EC 50 , 1 M), whereas oleic acid had no effect on TRPA1. 9-OA-NO 2 failed to activate TRPA1 in which the cysteines at positions 619, 639, and 663 and the lysine at 708 had been mutated. TRPA1 activation by 9-OA-NO 2 was not inhibited by the NO scavenger carboxy-PTIO. 9-OA-NO 2 had no effect on another nociceptive-specific ion channel, TRPV1. 9-OA-NO 2 activated a subset of mouse vagal and trigeminal sensory neurons, which also responded to the TRPA1 agonist allyl isothiocyanate and the TRPV1 agonist capsaicin. 9-OA-NO 2 failed to activate neurons derived from TRPA1(Ϫ/Ϫ) mice. The action of 9-OA-NO 2 at nociceptive nerve terminals was investigated using an ex vivo extracellular recording preparation of individual bronchopulmonary C fibers in the mouse. 9-OA-NO 2 evoked robust action potential discharge from capsaicin-sensitive fibers with slow conduction velocities (0.4 -0.7 m/s), which was inhibited by the TRPA1 antagonist AP-18. These data demonstrate that nitrooleic acid, a product of nitrative stress, can induce substantial nociceptive nerve activation through the selective and direct activation of TRPA1 channels.Oxidative stress and nitrative stress have been implicated as contributing to acute and chronic inflammation (Radi, 2004;Szabó et al., 2007;Valko et al., 2007). Nitric oxide (NO) is an endogenous mediator with multiple cellular functions that is produced by many cell types including vascular endothelium, neutrophils, fibroblasts, and nerves (Bian and Murad, 2003). NO, generated from L-arginine by NO synthases (NOS), reacts with the reactive oxygen species (ROS) superoxide-which is formed through multiple pathways in inflammation, including NADPH oxidase, xanthine oxidase, and perverted mitochondrial function-to produce the reactive nitrogen species (RNS), peroxynitrite (ONOOϪ), and nitrogen dioxide (*NO 2 ). RNS are potent inflammatory molecules that can react with lipids, proteins, and DNA (Szabó et al., 2007). Within membranes, where the hydrophobic environment maximizes RNS production (Möller et al., 2007), RNS react with unsaturated fatty acids (e.g., oleic acid), causing the addition of an NO 2 group (nitration) Jain et al., 2008;Trostchansky and Rubbo, 2008). Nitrated fatty acids (e.g., nitrooleic acid) are highly reactive electrophilic compounds that can modulate a variety of cellular targets, including thiol residues and peroxisome proliferator-activated receptor ␥ Trostchansky and Rubbo, 2008 ABBREVIATIONS: NOS, nitric-oxide ...

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Section: Discussionmentioning

confidence: 99%

“…All other chemicals were purchased from Sigma-Aldrich (St. Louis, MO). Because of the reported instability of 9-OA-NO 2 in aqueous solutions [half-life aq of approximately 2 h (Gorczynski et al, 2007)], 9-OA-NO 2 was dissolved into the appropriate buffer within 5 min of experimental use.…”

Section: Methodsmentioning

confidence: 99%

Nitrooleic Acid, an Endogenous Product of Nitrative Stress, Activates Nociceptive Sensory Nerves via the Direct Activation of TRPA1

Taylor‐Clark

Ghatta

Bettner³

et al. 2009

Mol Pharmacol

166

136

View full text Add to dashboard Cite

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“…Research in this field has demonstrated that NO 2 -FAs could occur in vivo as free fatty acids, esterified in complex lipids in hydrophobic compartments, and adducted with proteins-the latter two being the most abundant reservoirs (Schopfer et al, 2005a(Schopfer et al, , 2005bTrostchansky and Rubbo, 2008;Rudolph et al, 2009). Among NO 2 -FAs biological properties, the ability to release NO into aqueous environments has been considered a signaling mechanism of NO 2 -FAs as potent NO donors (Schopfer et al, 2005;Gorczynski et al, 2007). Furthermore, NO 2 -FAs predominantly act via posttranslational modification Geisler and Rudolph, 2012) in which the high electronegativity of NO 2 substituents, when bound to an alkenyl carbon of fatty acids, confers an electrophilic nature upon the adjacent carbon and enables a reversible Michael addition reaction with nucleophiles such as protein His and Cys residues by a process termed "nitroalkylation" (Baker et al, 2007).…”

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confidence: 99%

Nitro-Fatty Acids in Plant Signaling: Nitro-Linolenic Acid Induces the Molecular Chaperone Network in Arabidopsis

et al. 2015

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ORCID IDs: 0000-0002-6609-7242 (C.M.-P); 0000-0002-2210-9547 (B.S.-C.); 0000-0001-5284-8837 (J.J.-R.); 0000-0002-1814-9212 (F.J.C.); 0000-0002-9477-9195 (J.J.B.).Nitro-fatty acids (NO 2 -FAs) are the product of the reaction between reactive nitrogen species derived of nitric oxide (NO) and unsaturated fatty acids. In animal systems, NO 2 -FAs are considered novel signaling mediators of cell function based on a proven antiinflammatory response. Nevertheless, the interaction of NO with fatty acids in plant systems has scarcely been studied. Here, we examine the endogenous occurrence of nitro-linolenic acid (NO 2 -Ln) in Arabidopsis and the modulation of NO 2 -Ln levels throughout this plant's development by mass spectrometry. The observed levels of this NO 2 -FA at picomolar concentrations suggested its role as a signaling effector of cell function. In fact, a transcriptomic analysis by RNA-seq technology established a clear signaling role for this molecule, demonstrating that NO 2 -Ln was involved in plant defense response against different abiotic-stress conditions, mainly by inducing heat shock proteins and supporting a conserved mechanism of action in both animal and plant defense processes. Bioinformatics analysis revealed that NO 2 -Ln was also involved in the response to oxidative stress conditions, mainly depicted by H 2 O 2 , reactive oxygen species, and oxygen-containing compound responses, with a high induction of ascorbate peroxidase expression. Closely related to these results, NO 2 -Ln levels significantly rose under several abiotic-stress conditions such as wounding or exposure to salinity, cadmium, and low temperature, thus validating the outcomes found by RNA-seq technology. Jointly, to our knowledge, these are the first results showing the endogenous presence of NO 2 -Ln in Arabidopsis (Arabidopsis thaliana) and supporting the strong signaling role of these molecules in the defense mechanism against different abiotic-stress situations.

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“…1 Among the main properties of NO 2 -FAs, the ability to mediate different anti-inflammatory effects in animal systems is noteworthy, 2,3 thus being considered important mediators of cell signaling. Due to the chemical structure of NO 2 -FAs, these molecules have different biological properties, including the release of nitric oxide (NO) in aqueous mediums [4][5][6] and an electrophilic capacity allowing a reversible posttranslational modification. 7,8 Regarding the ability to release NO, basically 2 mechanisms of NO generation from NO 2 -FAs have been proposed, including a modified Nef reaction or by a nitroalkene-rearrangement.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Regarding the ability to release NO, basically 2 mechanisms of NO generation from NO 2 -FAs have been proposed, including a modified Nef reaction or by a nitroalkene-rearrangement. 4,6,9 Otherwise, the b-carbon adjacent to the nitro group (-NO 2 ) has a strong electrophilicity, representing a target for nucleophilic addition and thus generating a covalent bond with NO 2 -FAs by a reaction specifically termed nitroalkylation. In this sense, this electrophilic character allowing NO 2 -FAs to modulate key cellular targets has been widely reported, e.g., by the activation of the peroxisome proliferator-activated receptor (PPAR) or by the inhibition of nuclear factor-kappa B (NF-B).…”

Section: Introductionmentioning

confidence: 99%