Nitro-fatty acids: novel anti-inflammatory lipid mediators

Abstract

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.

Profiling and relative quantification of multiply nitrated and oxidized fatty acids

“…Increased levels of nitrolinoleic acid (LaNO 2 ) were detected in mitochondria during ischemic preconditioning, whereas the level of nitrooleic acid (OaNO 2 ) remained unchanged, indicating possible selectivity of fatty acid nitration [18]. Under inflammatory conditions LaNO 2 , OaNO 2 , and nitroarachidonic acid (AaNO 2 ) posses anti-inflammatory activities [19][20][21], including activation of peroxisome-proliferator-activated receptors [22] and nuclear factor E2 related factor 2 [23,24], induction of heme oxygenase 1 [25], inhibition of nuclear factor κB, and inhibition of prostaglandin endoperoxide H synthase (PGHS) [26] and NADPH oxidase [27]. OaNO 2 decreased superoxide production in activated macrophages and pulmonary artery smooth muscle cells, demonstrating protective effects in a hypoxia-induced murine model of pulmonary hypertension [28].…”

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

“…superoxide (O 2 .2 ), hydrogen peroxide (H 2 O 2 ), and lipid peroxyl radicals (LOO$)] in animal systems (Baker et al, 2004;Schopfer et al, 2005aSchopfer et al, , 2005bFreeman et al, 2008;Jain et al, 2008). However, the mechanism of fatty acid nitration in vivo remains unknown (Rubbo, 2013). The potential relevance of NO 2 -FAs as powerful signaling molecules in higher plants is based on a proven signaling capacity mediating antiinflammatory functions and cardiovascular benefits in animal systems (Cui et al, 2006;Kansanen et al, 2011).…”

Present knowledge and controversies, deficiencies, and misconceptions on nitric oxide synthesis, sensing, and signaling in plants

“…The reaction of NO and superoxide (O 2 − ) anion generates peroxynitrite (ONOO − ), which is a powerful nitrating agent able to cause tyrosine nitration of some proteins (Figure ; Gaupels, Spiazzi‐Vandelle, Yang, & Delledonne, ; Begara‐Morales et al, ). NO can react chemically with oxygen and generate nitrite and nitrate (Hancock, ) and, through a still unknown mechanism, can react with ROS and lipid peroxyl radical (LOO·) to produce nitrofatty acids (Rubbo, ; Figure ). Finally, the homeostasis of NO can also be regulated through its oxidization to nitrate by nonsymbiotic and truncated hemoglobins (HBs; Figure ).…”

“…Recently, the nitration of fatty acids by NO has also been demonstrated to be an important part of NO signaling in plants (Mata‐Pérez et al, ; Figure ). Several mechanisms have been described for nitrofatty acid synthesis but all of them involved radical ·NO 2 (Buchan, Bonacci, Fazzari, Salvatore, & Gelhaus Wendell, ; Rubbo, ). In plants, the regulatory roles of nitrofatty acids have been proposed to be related to their potential as NO donors and inducers of NO‐related PTMs in plants (Mata‐Pérez et al, ).…”