The focus of this proposed research is to define mechanisms underlying the production and reactions of .NO and peroxynitrite (ONOO-) with lipids and lipid radicals (LO. And LOO.) formed during membrane and lipoprotein oxidation. Special attention will also be paid to the direct reactions and indirect protective effects that .NO exerts towards the key membrane and lipoprotein antioxidants, alpha-tocopherol and ascorbate in chemical and cell studies. To understand the conditions and reactions underlying the dual protective and toxic aspects of the free radical reactivities of .NO, four experimental aims will be pursued to test the hypothesis that .NO can regulate oxidant/inflammatory injury in the vascular compartment by accelerating oxidative events via peroxynitrite (ONOO-) formation or alternatively, by chemically terminating free radical species. This will lead to modulation of inflammatory events and yield nitrogen-containing products having unique reactivities. Specifically, the principal investigator will 1) examine the reactions of .NO, reactive oxygen species and ONOO- with free and esterified unsaturated fatty acids (linoleic and arachidonic acids), 2) characterize the principal .NO/ONOO- derivatives of oxidized lipids (e.g. LONO/LNO2 and LOONO/LONO2 species) formed in oxidizing lipid systems and define their biochemical properties, 3) define the impact of .NO on integrated membrane and lipoprotein antioxidant defenses, focusing on the direct and indirect interactions of .NO with alpha-tocopherol, -tocopherol and ascorbic acid and 4) examine the actions of .NO in a cell model of oxidative and inflammatory injury. Successful accomplishment of the proposed aims will develop and solidify the concept that reactions between oxidized biomolecules and .NO a) mitigate pathologic events and b) yield reactive nitrogen-containing products. In particular, the principal investigator will reveal mechanisms and conditions underlying the dual capacity of .NO to mediate both tissue protection and injury, especially within the context of .NO serving as both a prooxidant and antioxidant species. The proposed research also provides a framework for the characterization of newly described lipid species that are formed during vascular inflammatory events.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Chemical Pathology Study Section (CPA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Freeman, Bruce A; O'Donnell, Valerie B; Schopfer, Francisco J (2018) The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling. Nitric Oxide 77:106-111
D'Amore, Antonio; Fazzari, Marco; Jiang, Hong-Bin et al. (2018) Nitro-Oleic Acid (NO2-OA) Release Enhances Regional Angiogenesis in a Rat Abdominal Wall Defect Model. Tissue Eng Part A 24:889-904
Woodcock, Chen-Shan Chen; Huang, Yi; Woodcock, Steven R et al. (2018) Nitro-fatty acid inhibition of triple-negative breast cancer cell viability, migration, invasion, and tumor growth. J Biol Chem 293:1120-1137
Verescakova, Hana; Ambrozova, Gabriela; Kubala, Lukas et al. (2017) Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages. Free Radic Biol Med 104:10-19
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
Rudolph, Tanja K; Ravekes, Thorben; Klinke, Anna et al. (2016) Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation. Cardiovasc Res 109:174-84
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
Ambrozova, Gabriela; Martiskova, Hana; Koudelka, Adolf et al. (2016) Nitro-oleic acid modulates classical and regulatory activation of macrophages and their involvement in pro-fibrotic responses. Free Radic Biol Med 90:252-260

Showing the most recent 10 out of 102 publications