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J. Biol. Chem., Vol. 280, Issue 51, 42464-42475, December 23, 2005

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Fatty Acid Transduction of Nitric Oxide Signaling

MULTIPLE NITRATED UNSATURATED FATTY ACID DERIVATIVES EXIST IN HUMAN BLOOD AND URINE AND SERVE AS ENDOGENOUS PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR LIGANDS^*

Paul R. S. Baker1, Yiming Lin¶23, Francisco J. Schopfer23, Steven R. Woodcock||, Alison L. Groeger, Carlos Batthyany, Scott Sweeney, Marshall H. Long, Karen E. Iles**4, Laura M. S. Baker1, Bruce P. Branchaud||, Yuqing E. Chen¶, and Bruce A. Freeman5

From the Departments of Anesthesiology, ^**Environmental Health Sciences and Center for Free Radical Biology, University of Alabama at Birmingham, Alabama 35294, the ^¶Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and the ^||Department of Chemistry, University of Oregon, Eugene, Oregon 97403

Mass spectrometric analysis of human plasma and urine revealed abundant nitrated derivatives of all principal unsaturated fatty acids. Nitrated palmitoleic, oleic, linoleic, linolenic, arachidonic and eicosapentaenoic acids were detected in concert with their nitrohydroxy derivatives. Two nitroalkene derivatives of the most prevalent fatty acid, oleic acid, were synthesized (9- and 10-nitro-9-cis-octadecenoic acid; OA-NO₂), structurally characterized and determined to be identical to OA-NO₂ found in plasma, red cells, and urine of healthy humans. These regioisomers of OA-NO₂ were quantified in clinical samples using ¹³C isotope dilution. Plasma free and esterified OA-NO₂ concentrations were 619 ± 52 and 302 ± 369 nM, respectively, and packed red blood cell free and esterified OA-NO₂ was 59 ± 11 and 155 ± 65 nM. The OA-NO₂ concentration of blood is 50% greater than that of nitrated linoleic acid, with the combined free and esterified blood levels of these two fatty acid derivatives exceeding 1 µM. OA-NO₂ is a potent ligand for peroxisome proliferator activated receptors at physiological concentrations. CV-1 cells co-transfected with the luciferase gene under peroxisome proliferator-activated receptor (PPAR) response element regulation, in concert with PPAR, PPAR, or PPAR expression plasmids, showed dose-dependent activation of all PPARs by OA-NO₂. PPAR showed the greatest response, with significant activation at 100 nM, while PPAR and PPAR were activated at 300 nM OA-NO₂. OA-NO₂ also induced PPAR -dependent adipogenesis and deoxyglucose uptake in 3T3-L1 preadipocytes at a potency exceeding nitrolinoleic acid and rivaling synthetic thiazo-lidinediones. These data reveal that nitrated fatty acids comprise a class of nitric oxide-derived, receptor-dependent, cell signaling mediators that act within physiological concentration ranges.

Received for publication, April 18, 2005 , and in revised form, September 23, 2005.

^* This work was supported in part by National Institutes of Health Grants HL58115 and HL64937 (to B. A. F.) and HL068878, HL075397, HL03676, and S06GM08248 (to Y. E. C.) and by American Heart Association Grant 0450118Z and a Department of Education GAANN (Graduate Assistance in Areas of National Need) award (to B. P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Both authors supported by National Institutes of Health Cardiovascular Hypertension Training Grant T32HL07457.

² These authors contributed equally to this manuscript.

³ Both authors supported by postdoctoral fellowships from the American Heart Association Southeast Affiliate.

⁴ Supported by a Parker B. Francis Fellowship in Pulmonary Research.

⁵ To whom correspondence should be addressed: Dept. of Anesthesiology and Center for Free Radical Biology, 304/8 Biomedical Research Bldg. II, 901 19th St. South, University of Alabama at Birmingham, Birmingham, AL 35233; Tel.: 205/934-4234; Fax: 205/934-7447; E-mail: freerad{at}uab.edu

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