title: CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function.
abstract: Inhibition of the cannabinoid receptor CB(1) (CB(1)-R) exerts numerous positive cardiovascular effects such as modulation of blood pressure, insulin sensitivity and serum lipid concentrations. However, direct vascular effects of CB(1)-R inhibition remain unclear. CB(1)-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 CB(1)-R antagonist rimonabant or vehicle for 7 weeks. CB(1)-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. CB(1)-R inhibition with rimonabant and AM251 led to down-regulation of angiotensin II type 1 receptor (AT1-R) expression, whereas stimulation with the CB(1)-R agonist CP 55,940 resulted in AT1-R up-regulation, indicating that AT1-R expression is directly regulated by the CB(1)-R. CB(2)-R inhibition had no impact on AT1-R expression in VSMC. Consistently, CB(1)-R inhibition decreased aortic AT1-R expression in vivo. CB(1)-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 CB(1)-R inhibition.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.
authors.forename: Vedat
authors.initials: V
authors.lastname: Tiyerili
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
authors.forename: Suzin
authors.initials: S
authors.lastname: Jung
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wassmann
authors.forename: Claas P
authors.initials: CP
authors.lastname: Naehle
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Sven
authors.initials: S
authors.lastname: Wassmann
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010880:Piperidines; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
chemical_list: D001057:Apolipoproteins E; D010880:Piperidines; D011720:Pyrazoles; D044140:Receptor, Angiotensin, Type 1; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant