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

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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.

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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.

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Authors and Affiliations

  1. Institute for Vascular Signalling, Centre for Molecular Medicine, Johann Wolfgang Goethe University and DZHK (German Centre for Cardiovascular Research) partner site Rhine-Main, Theodor Stern Kai 7, 60596, Frankfurt am Main, Germany

    Timo Frömel, Karin Kohlstedt, Rüdiger Popp, Khader Awwad, Eduardo Barbosa-Sicard & Ingrid Fleming

  2. King’s College London, King’s British Heart Foundation Centre, London, UK

    Xiaoke Yin & Manuel Mayr

  3. Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK

    Anita C. Thomas

  4. Institute of Pathology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

    Ralf Lieberz

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  1. Timo Frömel
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Correspondence to Ingrid Fleming.

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Frömel, T., Kohlstedt, K., Popp, R. et al. Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques. Basic Res Cardiol 108, 319 (2013). https://doi.org/10.1007/s00395-012-0319-8

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  • DOI: https://doi.org/10.1007/s00395-012-0319-8

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