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Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion

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Abstract

Thromboxane A2 (TXA2) is a potent prothrombotic and immune modulating lipid mediator, which is implicated in cardiovascular diseases, in particular, atherosclerotic lesion development and thrombogenicity. Here, we tested the hypothesis that thromboxane synthase (TXAS), the obligate enzyme required to synthesize TXA2, is expressed within the human atherosclerotic lesion, thus potentially contributing to TXA2 synthesis and disease development. In an animal study, different atherosclerosis-prone mouse strains were investigated and compared with control mice. In a patient study (n = 134), endarterectomies of carotid atherosclerotic lesions were compared with non-atherosclerotic arteries (n = 11). Expression of TXAS was evaluated by real-time quantitative reverse transcription PCR and immunohistochemistry. TXAS mRNA expression was increased within the vascular wall in mouse models of atherosclerosis with advanced lesions. In humans, TXAS was expressed in the atherosclerotic lesion, associated with increased inflammatory cells, in particular M2 polarized macrophages, and increased in atherosclerotic lesions of patients with recent symptoms of thrombotic events. Production of TXA2 by plaque tissue, verified by gas chromatography–mass spectrometry, increased after addition of arachidonic acid or lipopolysaccharide, and was inhibited by the TXAS inhibitor furegrelate. The findings suggest that intraplaque TXA2 generation may contribute to the development of atherosclerosis and its thrombotic complications in humans.

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Acknowledgements

These studies were supported by the Linneus Center for Research on Inflammation and Cardiovascular Disease of the Swedish Research Council and by grants from AFA health insurance company foundation, the Swedish Heart-Lung Foundation, Söderberg Foundation, The Swedish Research Council (6816-10350, 71X-14121, and 20854), the Konung Gustav V:s 80 årsfond, and EC FP6 (LSHM-CT-2004-005033). The report reflects only the author's views, and the European Commission is not liable for any use that may be made of the information herein. The work of A. Gabriele was supported by a European Union Marie Curie fellowship. The work of G. Paulsson-Berne was supported by the Swedish Research Council.

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The authors report no conflict of interest.

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Authors and Affiliations

  1. Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Anders Gabrielsen, Magnus Bäck, Anne-Louise Hemdahl, Hanna Agardh, Lasse Folkersen, Gabrielle Paulsson-Berne & Göran K. Hansson

  2. Division of Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Hong Qiu, Mats Hamberg & Jesper Z. Haeggström

  3. Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden

    Jesper Swedenborg & Ulf Hedin

  4. Center for Molecular Medicine, CMM L8:03, Karolinska Hospital, 17176, Stockholm, Sweden

    Anders Gabrielsen

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  1. Anders Gabrielsen
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Gabrielsen, A., Qiu, H., Bäck, M. et al. Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion. J Mol Med 88, 795–806 (2010). https://doi.org/10.1007/s00109-010-0621-6

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  • DOI: https://doi.org/10.1007/s00109-010-0621-6

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