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Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo

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Abstract

The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE−/− mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFβ were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of ‘de-novo’ atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.

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Abbreviations

ADP:

Adenosine diphosphate

OCT:

Optimal cutting temperature

DC:

Dendritic cells

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Conflict of interest

There are no conflicting financial interests, research support was obtained from the ELAN and IZKF -trust of the University of Erlangen-Nuernberg and the ADUMED-foundation, and no other funding source was employed.

Ethical standard

The study protocol was approved by the local animal research ethics committee and was conducted in accordance with the Helsinki Declaration.

Author information

Author notes

  1. Stephan M. Ensminger

    Present address: Heart and Diabetes Center NRW, Department of Thoracic and Cardiovascular Surgery, Ruhr-University Bochum, Georgstrasse 11, 32545, Bad Oeynhausen, Germany

Authors and Affiliations

  1. Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany

    Christian Heim, Julia Gebhardt, Martina Ramsperger-Gleixner, Michael Weyand & Stephan M. Ensminger

  2. Department of Nephrology, Friedrich-Alexander University, Erlangen-Nürnberg, Germany

    Johannes Jacobi

Authors
  1. Christian Heim
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  2. Julia Gebhardt
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Correspondence to Christian Heim.

Additional information

C. Heim and J. Gebhardt have contributed equally to this work.

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Heim, C., Gebhardt, J., Ramsperger-Gleixner, M. et al. Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo. Heart Vessels 31, 783–794 (2016). https://doi.org/10.1007/s00380-015-0696-7

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  • DOI: https://doi.org/10.1007/s00380-015-0696-7

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