Nitric oxide (.NO) mediates cell signaling via cGMP- and non-cGMP-dependent reactions and yields secondary oxides of nitrogen (NOx) that expand the range of molecular targets of .NO via oxidation, nitrosation and nitration reactions. The reactions of .NO and its products in hydrophobic tissue compartments (e.g., lipoproteins, membranes) also transduce .NO signaling. This research project focuses on identifying the specific chemical reactivities, biodistribution and signaling actions of nitrated fatty acids (generically termed """"""""NO2-FA""""""""). Current data support that NO2-FA represent inflammatory byproducts that serve as adaptive mediators of inflammation. Importantly, there remains a lack of knowledge regarding the structural properties and biochemical reactivities of NO2-FA that account for their induction of adaptive cell signaling responses. A central hypothesis provides focus to the proposed research plan: specifically, that nitro-fatty acids mediate adaptive cell signaling reactions that regulate metabolism and inflammation. This hypothesis will be tested by pursuing the following Specific Aims: #1. Synthesize and characterize selected nitro-fatty acid regioisomers;#2. Explore the mechanisms of PPAR receptor binding and activation by nitro-fatty acids;#3. Define the actions of nitro-fatty acids in an animal model of metabolic disease. Accomplishment of this research plan will fill the void in our current understanding of the chromatographic behavior, structural characteristics, reactivity and consequent in vitro and in vivo signaling actions of NO2-FA derivatives, thus better guiding the design of more efficacious pharmacologic modulators of metabolic and inflammatory signaling.

Public Health Relevance

This proposed research plan investigates the chemical biology and pharmacology of a new class of signaling mediators derived by the nitration of fatty acids. Clinically-significant signaling actions of these species will be explored by defining the basis for their unique and potent activation of the nuclear lipid receptor peroxisome proliferator activating receptor-3 (PPAR3) that is displayed by at least one facet of this class of signaling mediators. Overall, successful accomplishment of this innovative proposed study holds exciting new promise for the treatment of diseases associated with aging, such as arteriosclerosis, hypertension and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL058115-16
Application #
8320299
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Charette, Marc F
Project Start
2004-04-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
16
Fiscal Year
2012
Total Cost
$498,142
Indirect Cost
$169,336
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hughan, Kara S; Wendell, Stacy Gelhaus; Delmastro-Greenwood, Meghan et al. (2017) Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate. Hypertension :
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Diaz-Amarilla, Pablo; Miquel, Ernesto; Trostchansky, Andrés et al. (2016) Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation. Free Radic Biol Med 95:112-20
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Koudelka, Adolf; Ambrozova, Gabriela; Klinke, Anna et al. (2016) Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction. Cardiovasc Drugs Ther 30:579-586
Zhou, Chaoming; Ramaswamy, Swarna S; Johnson, Derrick E et al. (2016) Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling. Sci Rep 6:23416
Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana et al. (2016) Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition. Biochim Biophys Acta 1860:2428-2437
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

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