Eicosanoids and docosanoids have been shown to be involved in atherosclerosis. Polyunsaturated fatty acids (PUFAs) are important nutrients that are metabolized by lipoxygenases and cyclooxygenases to various mono-hydroxy metabolites which can be further metabolized by specific enzymes to more complex eicosanoids and docosanoids. In this study a high-performance liquid chromatography methodology was established and rabbits were fed with a control or a high-cholesterol diet to induce atherosclerotic lesions to determine pro- or anti-inflammatory lipid mediators in atherosclerotic vessels. In aortic samples from atherosclerotic rabbits we determined for the first time various eicosanoids/docosanoids and observed an increased concentration of 12-lipoxygenase metabolites. Increased levels of 12-hydroxyeicosatetraenoic acid (12-HETE) in high-cholesterol versus control animals as well as increased ratios of 12-HETE/arachidonic acid ratios indicate that 12-lipoxygenase metabolites may have importance in atherosclerosis. In addition, decreased concentrations of the 5-lipoxygenase metabolite leukotriene B4 levels were detected in high-cholesterol animals. A positive correlation of total plaque area with plasma levels of 12-HETE and a negative correlation with aortic levels of endogenous PPARγ-ligand 13-oxo-octadecadienoic acid were found. This study let us conclude that the cholesterol content in the diet might influence atherosclerosis via increased 12-lipoxygenase- and cyclooxygenase-mediated pathways and reduced 5-lipoxygenase pathways.

1.
Blaho VA, Buczynski MW, Brown CR, Dennis EA: Lipidomic analysis of dynamic eicosanoid responses during the induction and resolution of Lyme arthritis. J Biol Chem 2009;284:599-612.
2.
Buczynski MW, Dumlao DS, Dennis EA: Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology. J Lipid Res 2009;50:1015-1038.
3.
Shiraki T, Kamiya N, Shiki S, Kodama TS, Kakizuka A, Jingami H: Alpha, beta-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma. J Biol Chem 2005;280:14145-14153.
4.
Quehenberger O, Armando AM, Brown AH, et al: Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res 2010;51:3299-3305.
5.
Bannenberg G, Arita M, Serhan CN: Endogenous receptor agonists: resolving inflammation. ScientificWorldJournal 2007;7:1440-1462.
6.
Dennis EA, Deems RA, Harkewicz R, et al: A mouse macrophage lipidome. J Biol Chem 2010;285:39976-39985.
7.
Gomolka B, Siegert E, Blossey K, Schunck WH, Rothe M, Weylandt KH: Analysis of omega-3 and omega-6 fatty acid-derived lipid metabolite formation in human and mouse blood samples. Prostaglandins Other Lipid Mediat 2011;94:81-87.
8.
Yue H, Jansen SA, Strauss KI, et al: A liquid chromatography/mass spectrometric method for simultaneous analysis of arachidonic acid and its endogenous eicosanoid metabolites prostaglandins, dihydroxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and epoxyeicosatrienoic acids in rat brain tissue. J Pharm Biomed Anal 2007;43:1122-1134.
9.
Masoodi M, Mir AA, Petasis NA, Serhan CN, Nicolaou A: Simultaneous lipidomic analysis of three families of bioactive lipid mediators leukotrienes, resolvins, protectins and related hydroxy-fatty acids by liquid chromatography/electrospray ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom 2008;22:75-83.
10.
Kita Y, Takahashi T, Uozumi N, Shimizu T: A multiplex quantitation method for eicosanoids and platelet-activating factor using column-switching reversed-phase liquid chromatography-tandem mass spectrometry. Anal Biochem 2005;342:134-143.
11.
Galkina E, Ley K: Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 2009;27:165-197.
12.
Glass CK, Witztum JL: Atherosclerosis: the road ahead. Cell 2001;104:503-516.
13.
Yanni AE: The laboratory rabbit: an animal model of atherosclerosis research. Lab Anim 2004;38:246-256.
14.
Linton MF, Fazio S: Cyclooxygenase products and atherosclerosis. Drug Discov Today Ther Strateg 2008;5:25-36.
15.
Cipollone F, Cicolini G, Bucci M: Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. Pharmacol Ther 2008;118:161-180.
16.
Zhao L, Moos MP, Grabner R, et al: The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 2004;10:966-973.
17.
Burleigh ME, Babaev VR, Yancey PG, et al: Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. J Mol Cell Cardiol 2005;39:443-452.
18.
Wittwer J, Hersberger M: The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins Leukot Essent Fatty Acids 2007;77:67-77.
19.
Sears DD, Miles PD, Chapman J, et al: 12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice. PLoS One 2009;4:e7250.
20.
Reilly KB, Srinivasan S, Hatley ME, et al: 12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo. J Biol Chem 2004;279:9440-9450.
21.
Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 1998;93:229-240.
22.
Laffitte BA, Tontonoz P: Orphan nuclear receptors find a home in the arterial wall. Curr Atheroscler Rep 2002;4:213-221.
23.
Rühl R: Method to determine 4-oxo-retinoic acids, retinoic acids and retinol in serum and cell extracts by liquid chromatography/diode-array detection atmospheric pressure chemical ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom 2006;20:2497-2504.
24.
Kita Y, Takahashi T, Uozumi N, Nallan L, Gelb MH, Shimizu T: Pathway-oriented profiling of lipid mediators in macrophages. Biochem Biophys Res Commun 2005;330:898-906.
25.
Csanky E, Rühl R, Scholtz B, Vasko A, Takacs L, Hempel WM: Lipid metabolite levels of prostaglandin D2 and eicosapentaenoic acid recovered from bronchoalveolar lavage fluid correlate with lung function of chronic obstructive pulmonary disease patients and controls. Electrophoresis 2009;30:1228-1234.
26.
Lorenz M, Fechner M, Kalkowski J, et al: Effects of lycopene on the initial state of atherosclerosis in New Zealand White (NZW) rabbits. PLoS One 2012;7:e30808.
27.
Masoodi M, Nicolaou A: Lipidomic analysis of twenty-seven prostanoids and isoprostanes by liquid chromatography/electrospray tandem mass spectrometry. Rapid Commun Mass Spectrom 2006;20:3023-3029.
28.
Yang J, Eiserich JP, Cross CE, Morrissey BM, Hammock BD: Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients. Free Radic Biol Med 2012;53:160-171.
29.
Gertow K, Nobili E, Folkersen L, et al: 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms. Atherosclerosis 2011;215:411-416.
30.
Jacob S, Laury-Kleintop L, Lanza-Jacoby S: The select cyclooxygenase-2 inhibitor celecoxib reduced the extent of atherosclerosis in apo E-/- mice. J Surg Res 2008;146:135-142.
31.
Zagryagskaya AN, Aleksandrov DA, Pushkareva MA, Galkina SI, Grishina ZV, Sud'ina GF: Biosynthesis of leukotriene B4 in human polymorphonuclear leukocytes: regulation by cholesterol and other lipids. J Immunotoxicol 2008;5:347-352.
32.
Spanbroek R, Grabner R, Lotzer K, et al: Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci USA 2003;100:1238-1243.
33.
Qiu H, Gabrielsen A, Agardh HE, et al: Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci USA 2006;103:8161-8166.
34.
Cao RY, St Amand T, Grabner R, Habenicht AJ, Funk CD: Genetic and pharmacological inhibition of the 5-lipoxygenase/leukotriene pathway in atherosclerotic lesion development in ApoE deficient mice. Atherosclerosis 2009;203:395-400.
35.
Ceriello A: Thiazolidinediones as anti-inflammatory and anti-atherogenic agents. Diabetes Metab Res Rev 2008;24:14-26.
36.
Tikellis C, Jandeleit-Dahm KA, Sheehy K, et al: Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules. Atherosclerosis 2008;199:55-64.
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