Activation of stress signaling pathways by oxidized and nitrated lipids

Oxygen and nitric oxide-derived reactive species at high concentrations can mediate the oxidation of macromolecules such as lipids, thereby contributing to disease pathology. At lower rates of generation, the oxidation and nitration of free or phospholipid-esterified unsaturated fatty acids also mediate more subtle, specific and highly-evolved cell signaling reactions. Notably, electrophilic products of unsaturated fatty acid oxidation and nitration can elicit cytoprotective responses such as those regulated by the Keap1-Nrf2-ARE pathway. The molecular characteristics of lipid-derived signaling mediators that define their ability to trigger stress signaling responses is constrained by their protein targets within the signaling pathways. Recent findings on the Nrf2-activating properties of nitrated fatty acids will be presented, with special reference to interactions with the endothelin signaling system. The functionally significant interactions of Keap1-Nrf2-ARE-mediated signaling with other stress signaling pathways, interrogated utilizing novel genome-wide deep sequencing methods, is also discussed in the context of electrophilic fatty acid signaling. Interrogating the stress signaling pathways elicited by electrophilic lipid mediators will yield important insights into their signaling functions, which ultimately leads to better understanding of the pathogenesis of cardiovascular diseases and the potential for lipid-derived electrophiles as therapeutic agents.