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Basic Research in Cardiology

, 108:319 | Cite as

Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques

  • Timo Frömel
  • Karin Kohlstedt
  • Rüdiger Popp
  • Xiaoke Yin
  • Khader Awwad
  • Eduardo Barbosa-Sicard
  • Anita C. Thomas
  • Ralf Lieberz
  • Manuel Mayr
  • Ingrid FlemingEmail author
Original Contribution

Abstract

Cytochrome P450 (CYP) epoxygenases metabolize endogenous polyunsaturated fatty acids to their corresponding epoxides, generating bioactive lipid mediators. The latter play an important role in vascular homeostasis, angiogenesis, and inflammation. As little is known about the functional importance of extra-vascular sources of lipid epoxides, we focused on determining whether lipid epoxide-generating CYP isoforms are expressed in human monocytes/macrophages. Epoxides were generated by freshly isolated human monocytes and production increased markedly during differentiation to macrophages. Mass spectrometric analysis identified CYP2S1 as a novel macrophage CYP and CYP2S1-containing microsomes generated epoxides of arachidonic, linoleic and eicosapentaenoic acid. Macrophage CYP2S1 expression was increased by LPS and IFN-γ (classically activated), and oxidized LDL but not IL-4 and IL-13 (alternatively activated), and was colocalised with CD68 in inflamed human tonsils but not in breast cancer metastases. Prostaglandin (PG) E2 is an immune modulator factor that promotes phagocytosis and CYP2S1 can metabolize its immediate precursors PGG2 and PGH2 to 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). We found that CYP inhibition and siRNA-mediated downregulation of CYP2S1 increased macrophage phagocytosis and that the latter effect correlated with decreased 12-HHT formation. Although no Cyp2s1 protein was detected in aortae from wild-type mice it was expressed in aortae and macrophage foam cells from ApoE−/− mice. Consistent with these observations CYP2S1 was colocalised with the monocyte marker CD68 in human atherosclerotic lesions. Thus, CYP2S1 generates 12-HHT and is a novel regulator of macrophage function that is expressed in classical inflammatory macrophages, and can be found in murine and human atherosclerotic plaques.

Keywords

Epoxygenase Linoleic acid Macrophage polarization Omega 3 fatty acids Phagocytosis 

Notes

Acknowledgments

The authors are indebted to Marie von Reutern for expert technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (SFB-TR 23/A6 and Exzellenzcluster 147 “Cardio-Pulmonary Systems”) and by the European Vascular Genomic Network, a Network of Excellence supported by the European Community’s sixth Framework Program (Contract N° LSHM-CT-2003-503254). M.M. is a Senior Fellow of the British Heart Foundation.

Conflict of interest

The authors have no disclosures to declare.

Supplementary material

395_2012_319_MOESM1_ESM.pdf (108 kb)
Supplementary material 1 (PDF 107 kb)
395_2012_319_MOESM2_ESM.pdf (140 kb)
Supplementary material 2 (PDF 139 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Timo Frömel
    • 1
  • Karin Kohlstedt
    • 1
  • Rüdiger Popp
    • 1
  • Xiaoke Yin
    • 2
  • Khader Awwad
    • 1
  • Eduardo Barbosa-Sicard
    • 1
  • Anita C. Thomas
    • 3
  • Ralf Lieberz
    • 4
  • Manuel Mayr
    • 2
  • Ingrid Fleming
    • 1
    Email author
  1. 1.Institute for Vascular Signalling, Centre for Molecular MedicineJohann Wolfgang Goethe University and DZHK (German Centre for Cardiovascular Research) partner site Rhine-MainFrankfurt am MainGermany
  2. 2.King’s College London, King’s British Heart Foundation CentreLondonUK
  3. 3.Bristol Heart InstituteUniversity of Bristol, Bristol Royal InfirmaryBristolUK
  4. 4.Institute of PathologyJohann Wolfgang Goethe UniversityFrankfurt am MainGermany

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