title: The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice.
abstract: BACKGROUND
  We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.
  
  
  METHODS
  Forty-eight apolipoprotein E-deficient (ApoE-/-) mice were kept on a 16-week high-fat diet. Mice were then placed on a normal diet and were randomized to the following groups with n=12 mice for 6 more weeks: 1) Control (Co) - no intervention; 2) Exercise (Ex) - exercise training on treadmill; 3) Rimonabant (Ri) - oral administration of rimonabant (10 mg/kg/day); or 4) Rimonabant+Exercise (RiEx) - combination of Ri and Ex groups treatment. At the end, all animals were sacrificed, and blood samples, as well as aortic root specimens, were obtained for histomorphometric analysis and quantification of the serum and plaque content of matrix metalloproteinases (MMPs).
  
  
  RESULTS
  The mean plaque area was significantly smaller (RiEx: 43.18±1.72%, Ri: 44.66±3.1%, Ex: 49±4.10%, Co: 70.43±2.83%) in all active treatment groups relative to the Co group (p<0.01). Conversely, the relative concentrations of collagen and elastin were increased significantly across all treatment groups compared to Co (p<0.05). Immunohistochemical analysis revealed significantly reduced macrophage content within plaques after all interventions, with the most pronounced effect observed after combined treatment (RiEx: 9.4±3.92%, Ri: 15±2.45%, Ex: 19.78±2.79%, Co: 34.25±4.99%; p<0.05). Within plaques, the TIMP-1 concentration was significantly upregulated in exercise-treated groups. MMP-3 and MMP-9 concentrations were equivalently decreased in all three active treatment groups compared to controls (p<0.001).
  
  
  CONCLUSIONS
  Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.
authors.affiliation: Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece. Electronic address: mkatsiboulas@bioacademy.gr.
authors.forename: Michalis
authors.initials: M
authors.lastname: Katsimpoulas
authors.affiliation: Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Kadoglou
authors.affiliation: Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Petros
authors.initials: P
authors.lastname: Moustardas
authors.affiliation: Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Alkistis
authors.initials: A
authors.lastname: Kapelouzou
authors.affiliation: Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Dede
authors.affiliation: Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kostomitsopoulos
authors.affiliation: Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Panayotis E
authors.initials: PE
authors.lastname: Karayannacos
authors.affiliation: Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
authors.forename: Alkiviadis
authors.initials: A
authors.lastname: Kostakis
authors.affiliation: Department of Vascular Surgery, Medical School, University of Athens, Greece.
authors.forename: Christos D
authors.initials: CD
authors.lastname: Liapis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D063388:Endocannabinoids / Q000008:administration & dosage* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000379:methods*; D010880:Piperidines / Q000008:administration & dosage* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000628:therapy*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D011897:Random Allocation; D000077285:Rimonabant; D016896:Treatment Outcome
chemical_list: D001057:Apolipoproteins E; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D020782:Matrix Metalloproteinases; D000077285:Rimonabant
keywords: Cannabinoid Receptor 1; atherosclerosis; matrix metalloproteinases