title: Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice.
abstract: OBJECTIVE
  WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediatedviaCB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene.
  
  
  METHODS
  After 6 weeks on an atherogenic diet, groups of CB2+/+and CB2-/-Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified.
  
  
  RESULTS
  Plasma cholesterol and triglyceride levels did not differ between CB2+/+and CB2-/-mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2+/+and CB2-/-mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2+/+and CB2-/-mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2+/+mice, and lesional smooth muscle content in both CB2+/+and CB2-/-mice. Lesional apoptosis was also greater in CB2+/+mice compared to CB2-/-mice, and only reduced by WIN55,212-2 in CB2+/+mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2.
  
  
  CONCLUSIONS
  WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularityviaCB2-dependent and CB2-independent mechanisms.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Netherland-Van Dyke
authors.affiliation: Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
authors.forename: Ward
authors.initials: W
authors.lastname: Rodgers
authors.affiliation: Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
authors.forename: Makenzie
authors.initials: M
authors.lastname: Fulmer
authors.affiliation: Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Lahr
authors.affiliation: Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thewke
keywords: Atherosclerosis; Cannabinoid Receptor; WIN55,212-2