Activation of Stress Signaling Pathways by Oxidized and Nitrated Lipids

P15 Inflammation-Related Gene Expression by Lipid Oxidation Derived Products in the Progression of Atherosclerosis Giuseppe Poli1, Gabriella Leonarduzzi1, Simona Gargiulo1, Paola Gamba1, Barbara Sottero1, Cinzia Mascia1, and Fiorella Biasi1, 1University of Turin, Italy Inflammation is unanimously recognized as primary driving force in both initiation and progression of major human chronic diseases. In these pathologies inflammation is constantly associated with oxidative stress and lipid oxidation. With regard to atherosclerosis, inflammatory reactions in the arterial wall are triggered and sustained by a wide spectrum of stimuli, like hyperglycemia, hypercholesterolemia, smoking, hypertension, that are often, if not always, associated with significant changes of redox equilibrium in vascular cells. Such redox imbalance certainly favors transmigration of blood inflammatory cells and LDL particles in the artery’s sub-intimal space. Among the different oxidation products of LDL lipid moiety, oxidized phospholipids, unesterified aldehydes and oxidized cholesterol have been shown to consistently accumulate in atherosclerotic lesions, and are considered as likely involved in the promotion of the monocytic inflammation that underlies atherosclerosis. Of these three classes of LDL lipid oxidation derivatives, we mainly focused on 4-hydroxy-trans-2-nonenal (HNE) and oxysterols and investigated their pro-inflammatory and pro-atherogenic effects as well as related signaling transduction and modulation of gene expression. Both HNE and oxysterols appear, certainly with other pro-inflammatory mediators, as primarily involved in the multistep process of atherosclerosis, from initial endothelial cell damage to plaque formation and development.

Giuseppe Poli

doi:10.1016/j.freeradbiomed.2010.10.679

P16 Activation of Stress Signaling Pathways by Oxidized and Nitrated Lipids Anna-Liisa Levonen, University of Eastern Finland 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 oxidized phospholipids and nitrated fatty acids will be presented, with special reference to inflammatory and cardiovascular disease processes. The functionally significant interactions of Keap1-Nrf2ARE-mediated signaling with other stress signaling pathways, including the heat shock response (HSR) and unfolded protein response (UPR), is also discussed in the context of electrophilic fatty acid signaling. Given that the formation of lipid derived electrophiles is increased in diverse inflammatory conditions, these findings have important implications in the pathogenesis and treatment of cardiovascular diseases.

Anna-Liisa Levonen

doi:10.1016/j.freeradbiomed.2010.10.680

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