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Quantitative profiling of oxylipins in plasma and atherosclerotic plaques of hypercholesterolemic rabbits

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Abstract

Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) that affect a broad range of physiological processes, including cell proliferation, inflammation, inflammation resolution, and vascular function. Moreover, oxylipins are readily detectable in plasma, and certain subsets of oxylipins have been detected in human atherosclerotic lesions. Taken together, we set out to produce a detailed quantitative assessment of plasma and plaque oxylipins in a widely used model of atherosclerosis, to identify potential biomarkers of disease progression. We administered regular chow or regular chow supplemented with 0.5 % cholesterol (HC) to male New Zealand white rabbits for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our targeted lipidomic analyses of oxylipins on plaques isolated from rabbits fed the HC diet detected 34 oxylipins, 28 of which were in compliance with our previously established quality control acceptance criteria. The arachidonic acid (AA) metabolite derived from the COX pathway, 6-keto-PGF1α was the most abundant plaque oxylipin, followed by the linoleic acid (LA) metabolites 9-HODE, 13-HODE and 9,12,13-TriHOME and the arachidonic acid (AA)-derivatives 11-HETE and 12-HETE. We additionally found that the most abundant oxylipins in plasma were three of the five most abundant oxylipins in plaque, namely 11-HETE, 13-HODE, and 9-HODE. The studies reported here make the first step towards a comprehensive characterization of oxylipins as potentially translatable biomarkers of atherosclerosis.

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Abbreviations

AA 20:4 n-6:

Arachidonic acid

ALA 18:3 n-3:

Polyunsaturated fatty acid precursors to oxylipin synthesis: alpha-linoleic acid

DHA 22:6 n-3:

Docosahexaenoic acid

DiHDPEs:

Dihydroxydocosapentaenoic acids

DiHETEs:

Dihydroxyeicosatetraenoic acids

DiHETrEs:

Dihydroxyeicosatrienoic acids

DiHODEs:

Dihydroxyoctadecadienoic acids

DiHOMEs:

Dihydroxyoctadecenoic acids

EPA 20:5 n-6:

Eicosapentaenoic acid

EpDPEs:

Epoxydocosapentaenoic acids

EpETEs:

Epoxyeicosatetraenoic acids

EpETrEs:

Epoxyeicosatrienoic acids

EpODEs:

Epoxyoctadecadienoic acids

EpOMEs:

Epoxyoctadecenoic acids

HDoHEs:

Hydroxydocosahexaenoic acids

HEPEs:

Hydroxyeicosapentaenoic acids

HETEs:

Hydroxyeicosatetraenoic acids

HODEs:

Hydroxyoctadecadienoic acids

HOTrEs:

Hydroxyoctadecatrienoic acids

LA 18:2 n-6:

Linoleic acid

PGs:

Products of polyunsaturated fatty acid metabolism: prostaglandins

TXBs:

Thromboxanes

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Acknowledgments

The authors thank the MRL Postdoctoral Fellowship Program for financial support. L.A.B. is supported by a research fellowship provided by the MRL Postdoctoral fellowship program. The manuscript was written through contributions from all authors. All authors have given approval to the final version of the manuscript.

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Authors and Affiliations

  1. Merck and Co., Inc, Merck Research Laboratories, Kenilworth, NJ, 07033, USA

    Lazar A. Bojic, David G. McLaren, Sheng-Ping Wang, Ray Rosa, Stephen F. Previs, Douglas G. Johns & Jose M. Castro-Perez

  2. Leiden Amsterdam Centre for Drug Research, Netherlands Metabolomics Centre, 2300 LA, Leiden, The Netherlands

    Amy C. Harms, Thomas Hankemeier & Adrie Dane

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  1. Lazar A. Bojic
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  2. David G. McLaren
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Correspondence to Lazar A. Bojic.

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Bojic, L.A., McLaren, D.G., Harms, A.C. et al. Quantitative profiling of oxylipins in plasma and atherosclerotic plaques of hypercholesterolemic rabbits. Anal Bioanal Chem 408, 97–105 (2016). https://doi.org/10.1007/s00216-015-9105-4

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  • DOI: https://doi.org/10.1007/s00216-015-9105-4

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