Convergence of nitric oxide and lipid signaling: Anti-inflammatory nitro-fatty acids |
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| Authors: | Paul RS Baker Francisco J Schopfer Valerie B O’Donnell Bruce A Freeman |
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| Institution: | 1. University of Pittsburgh School of Medicine, Department of Pharmacology & Chemical Biology, E1340 Thomas E. Starzl Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA;2. Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;1. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA;2. Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh PA, 15261, USA;3. Pharmaceutical Development Section, Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA;1. Biochemistry and Cell Signaling in Nitric Oxide Group, Department of Experimental Biology, Center for Advanced Studies in Olive Grove and Olive Oils, Faculty of Experimental Sciences, Campus Universitario “Las Lagunillas” s/n, University of Jaén, E-23071, Jaén, Spain;2. Department of Inorganic and Organic Chemistry, Faculty of Experimental Sciences, Campus Universitario “Las Lagunillas” s/n, University of Jaén, E-23071, Jaén, Spain;1. Institut des Biomolécules Max Mousseron IBMM – UMR 5247 – CNRS – UM – ENSCM, Faculté de pharmacie 15, Avenue Charles Flahault, 34060 Montpellier CEDEX 2, France;2. Sorbonne Université, CNRS, Integrative Biology of Marine Models (LBI2M), Station Biologique de Roscoff (SBR), 29680 Roscoff, France;1. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA;2. Complexa Inc. Berwyn, PA, USA |
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| Abstract: | The signaling mediators nitric oxide (˙NO) and oxidized lipids, once viewed to transduce metabolic and inflammatory information via discrete and independent pathways, are now appreciated as interdependent regulators of immune response and metabolic homeostasis. The interactions between these two classes of mediators result in reciprocal control of mediator sythesis that is strongly influenced by the local chemical environment. The relationship between the two pathways extends beyond coregulation of ˙NO and eicosanoid formation to converge via the nitration of unsaturated fatty acids to yield nitro derivatives (NO2-FA). These pluripotent signaling molecules are generated in vivo as an adaptive response to oxidative inflammatory conditions and manifest predominantly anti-inflammatory signaling reactions. These actions of NO2-FA are diverse, with these species serving as a potential chemical reserve of ˙NO, reacting with cellular nucleophiles to posttranslationally modify protein structure, function, and localization. In this regard these species act as potent endogenous ligands for peroxisome proliferator-activated receptor γ. Functional consequences of these signaling mechanisms have been shown in multiple model systems, including the inhibition of platelet and neutrophil functions, induction of heme oxygenase-1, inhibition of LPS-induced cytokine release in monocytes, increased insulin sensitivity and glucose uptake in adipocytes, and relaxation of preconstricted rat aortic segments. These observations have propelled further in vitro and in vivo studies of mechanisms of NO2-FA signaling and metabolism, highlighting the therapeutic potential of this class of molecules as anti-inflammatory drug candidates. |
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