Atherosclerosis accounts for three fourth of all deaths from cardiovascular disease and atherothrombotic diseases are projected to be the leading cause of death worldwide in 2020, representing a major health burden. Omega-3 (w-3) polyunsaturated fatty acids exert potent anti-inflammatory actions and beneficial cardiovascular effects. Although these properties are widely recognized, the underlying mechanisms remain largely unknown. An electrophilic mapping of lipids formed during macrophage activation showed that keto-derived w-3 fatty acids omega 3 derived-fatty acids were present at intracellular concentrations up to 200 nM. The formation of these species was dependent on COX-2, and administered aspirin increased the levels of these w-3 electrophilic fatty acid oxo-derivatives (EFOX). Recently, EFOX have been shown to be formed in human macrophages, neutrophils and animal tissues subjected to inflammation. Additionally, EFOX have been found to form glutathione and protein adducts and to modulate the inflammatory pathways through activation of Nrf2 pathway, inhibition of cytokine expression and reduction of inducible nitric oxide synthase levels. The hypothesis of this proposal is that EFOX are biologically relevant molecules with anti-atherogenic properties formed during inflammation and atherosclerosis that transduce the beneficial effects of w-3 fatty acids and aspirin through the electrophilic regulation of signaling pathways. To address this hypothesis we propose to chemically generate analytical tools (i.e. deuterated and labeled standards) to aid in the rigorous biological identification and quantitation of EFOX. These standards will be used for the analysis of biosynthetic pathways in macrophages and to assess the in vivo formation in a relevant murine model of atherosclerosis. The biochemical and signaling properties of these species and its targets will be analyzed using cellular models. Finally, the pharmacological effects of EFOX will be tested on a murine atherosclerosis model. At completion, we expect to have determined the different EFOX isomeric species and their in vivo relevance and formation. In addition, we expect to have gained a clear understanding of their electrophilic reactivities, modulation of phase 2 gene expression, in particular the Nrf2/KEAP1 pathway and their PPARg activation. It is expected that this proposal will lead to a better understanding of w-3 fatty acid effects and to improved pharmacological approaches to decrease atherosclerosis and its detrimental effects.
Atherosclerosis is responsible for over 500,000 deaths per year in the United States. Omega-3 polyunsaturated fatty acids, commonly found in fish oil, exert potent anti-inflammatory actions and beneficial cardiovascular effects although the operative mechanisms remain largely unknown. We recently discovered the formation of novel anti-inflammatory lipids called EFOX by human macrophages and neutrophils during inflammation. We propose to characterize the biochemical functionalities of these species and their effects and levels during atherosclerosis. It is expected that the results will not only increase our understanding of this disease, but also allow for a better design of pharmacological approaches for its treatment.
|Villacorta, Luis; Minarrieta, Lucia; Salvatore, Sonia R et al. (2018) In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation. Redox Biol 15:522-531|
|Prentice, Kacey J; Wendell, Stacy G; Liu, Ying et al. (2018) CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis. EBioMedicine 27:200-213|
|Khoo, Nicholas K H; Li, Lihua; Salvatore, Sonia R et al. (2018) Electrophilic fatty acid nitroalkenes regulate Nrf2 and NF-?B signaling:A medicinal chemistry investigation of structure-function relationships. Sci Rep 8:2295|
|Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R et al. (2017) Nitro-fatty acid pharmacokinetics in the adipose tissue compartment. J Lipid Res 58:375-385|
|Salvatore, Sonia R; Vitturi, Dario A; Fazzari, Marco et al. (2017) Evaluation of 10-Nitro Oleic Acid Bio-Elimination in Rats and Humans. Sci Rep 7:39900|
|Villacorta, Luis; Gao, Zhen; Schopfer, Francisco J et al. (2016) Nitro-fatty acids in cardiovascular regulation and diseases: characteristics and molecular mechanisms. Front Biosci (Landmark Ed) 21:873-89|
|Koenitzer, Jeffrey R; Bonacci, Gustavo; Woodcock, Steven R et al. (2016) Fatty acid nitroalkenes induce resistance to ischemic cardiac injury by modulating mitochondrial respiration at complex II. Redox Biol 8:1-10|
|Vitturi, Dario A; Minarrieta, Lucia; Salvatore, Sonia R et al. (2015) Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride. Nat Chem Biol 11:504-10|
|Fazzari, Marco; Khoo, Nicholas; Woodcock, Steven R et al. (2015) Generation and esterification of electrophilic fatty acid nitroalkenes in triacylglycerides. Free Radic Biol Med 87:113-24|
|Fazzari, Marco; Trostchansky, Andrés; Schopfer, Francisco J et al. (2014) Olives and olive oil are sources of electrophilic fatty acid nitroalkenes. PLoS One 9:e84884|
Showing the most recent 10 out of 20 publications