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CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function

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Abstract

Inhibition of the cannabinoid receptor CB1 (CB1-R) exerts numerous positive cardiovascular effects such as modulation of blood pressure, insulin sensitivity and serum lipid concentrations. However, direct vascular effects of CB1-R inhibition remain unclear. CB1-R expression was validated in vascular smooth muscle cells (VSMCs) and aortic tissue of mice. Apolipoprotein E-deficient (ApoE−/−) mice were treated with cholesterol-rich diet and the selective CB1-R antagonist rimonabant or vehicle for 7 weeks. CB1-R inhibition had no effect on atherosclerotic plaque development, collagen content and macrophage infiltration but led to improved aortic endothelium-dependent vasodilation and decreased aortic reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of cultured VSMC with rimonabant resulted in reduced angiotensin II-mediated but not basal ROS production and NADPH oxidase activity. CB1-R inhibition with rimonabant and AM251 led to down-regulation of angiotensin II type 1 receptor (AT1-R) expression, whereas stimulation with the CB1-R agonist CP 55,940 resulted in AT1-R up-regulation, indicating that AT1-R expression is directly regulated by the CB1-R. CB2-R inhibition had no impact on AT1-R expression in VSMC. Consistently, CB1-R inhibition decreased aortic AT1-R expression in vivo. CB1-R inhibition leads to decreased vascular AT1-R expression, NADPH oxidase activity and ROS production in vitro and in vivo. This antioxidative effect is associated with improved endothelial function in ApoE−/− mice, indicating beneficial direct vascular effects of CB1-R inhibition.

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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG) and by an unrestricted research grant from Sanofi-Aventis. The excellent technical assistance of Isabel Paez-Maletz, Annika Bohner, Kathrin Paul, Susanne Schnell and Anja Kerksiek is greatly appreciated.

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Authors and Affiliations

  1. Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Vedat Tiyerili, Sebastian Zimmer, Suzin Jung, Kerstin Wassmann, Georg Nickenig & Sven Wassmann

  2. Radiologische Klinik, Universitätsklinikum Bonn, Bonn, Germany

    Claas P. Naehle

  3. Institut für Klinische Chemie und Pharmakologie, Universitätsklinikum Bonn, Bonn, Germany

    Dieter Lütjohann

  4. Institut für Molekulare Psychiatrie, Universitätsklinikum Bonn, Bonn, Germany

    Andreas Zimmer

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  1. Vedat Tiyerili
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  2. Sebastian Zimmer
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  3. Suzin Jung
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  9. Sven Wassmann
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Correspondence to Sven Wassmann.

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V. Tiyerili and S. Zimmer contributed equally to this study.

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Tiyerili, V., Zimmer, S., Jung, S. et al. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol 105, 465–477 (2010). https://doi.org/10.1007/s00395-010-0090-7

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  • DOI: https://doi.org/10.1007/s00395-010-0090-7

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