Basic Research in Cardiology

, Volume 105, Issue 4, pp 465–477

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

  • Vedat Tiyerili
  • Sebastian Zimmer
  • Suzin Jung
  • Kerstin Wassmann
  • Claas P. Naehle
  • Dieter Lütjohann
  • Andreas Zimmer
  • Georg Nickenig
  • Sven Wassmann
Original Contribution

DOI: 10.1007/s00395-010-0090-7

Cite this article as:
Tiyerili, V., Zimmer, S., Jung, S. et al. Basic Res Cardiol (2010) 105: 465. doi:10.1007/s00395-010-0090-7

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.

Keywords

Rimonabant AT1 receptor CB1 receptor Oxidative stress Endothelial function 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Vedat Tiyerili
    • 1
  • Sebastian Zimmer
    • 1
  • Suzin Jung
    • 1
  • Kerstin Wassmann
    • 1
  • Claas P. Naehle
    • 2
  • Dieter Lütjohann
    • 3
  • Andreas Zimmer
    • 4
  • Georg Nickenig
    • 1
  • Sven Wassmann
    • 1
  1. 1.Medizinische Klinik und Poliklinik IIUniversitätsklinikum BonnBonnGermany
  2. 2.Radiologische KlinikUniversitätsklinikum BonnBonnGermany
  3. 3.Institut für Klinische Chemie und PharmakologieUniversitätsklinikum BonnBonnGermany
  4. 4.Institut für Molekulare PsychiatrieUniversitätsklinikum BonnBonnGermany