ABSTRACT
Nitration of biomolecules represents a key biologically relevant redox signaling and injury event. There is a wide array of chemical reactions that might lead to nitration of targets, including proteins, lipids, and DNA, linked to overproduction of reactive nitrogen species (RNS) derived from the interaction of nitric oxide (i NO) with reactive oxygen species (ROS). Since production of RNS is intimately connected with oxidative stress, this condition is referred as nitro-oxidative stress. Reactions involving synthesis of RNS are very relevant to pathophysiology since they lead to removal of the endothelial-derived relaxing factor (EDRF) from the vasculature, critical for regulation of vascular tone. In the last decade, biological nitration has
Introduction ............................................................................................................ 101 Lipid Nitration ....................................................................................................... 102
Mechanisms of Fatty Acid Nitration: Chemical and Cell Synthesis of Nitroalkenes .................................................................................................. 103 Characterization and Identication of Nitro-Fatty Acids by Mass Spectrometry ............................................................................................ 104 Electrophilicity of Nitro-Fatty Acids: Cell Signaling Anti-Inammatory Properties........................................................................................................... 106 Modulation of the Production of Reactive Species: Nitric Oxide Synthase and NADPH Oxidase ........................................................................................ 108 Nitric Oxide and Arachidonic Acid Signaling are Linked through Nitro-Fatty Acids: Modulation of Prostaglandin Endoperoxide H Synthase ..... 110
In Vivo Detection and Therapeutic Potential of Nitrated Lipids ............................ 110 Potential Pitfalls ..................................................................................................... 111 Abbreviations ......................................................................................................... 112 Acknowledgments .................................................................................................. 113 Author Disclosure Statement ................................................................................. 113 References .............................................................................................................. 113
also been reported to modulate lipid activity in a physiologically relevant way. In fact, nitration of aliphatic compounds has been a subject of interest in organic chemistry since the early nineteenth century. Nonetheless, it was only recently linked to the pathobiological conditions associated with inammation and nitro-oxidative stress; alongside with the breakthrough of i NO identication as the EDRF came the acknowledgment that RNS participate in physiological processes involving modi- cation of cellular targets. Lipid nitration gained biological relevance in the 1990s as a potential pathway for nitro-oxidative modication of biological molecules. In 2002, for the rst time, nitrated derivatives of linoleic acid were detected in the plasma of healthy individuals (Lima et al. 2002). Moreover, increased concentrations of these nitro-derivatives were found in hyperlipidemic donors, thus reinforcing their biological relevance and positioning nitro-fatty acids (nitroalkenes, NO2-FA) as potential footprints for nitro-oxidative damage in human disease. At this time, the current hypothesis promotes that NO2-FA may represent redox signaling mediators that are able to modulate a variety of cell signaling pathways.
