The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in apo-E-deficient mice

Introduction: 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 highfat 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) RimonabantþExercise (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). Discussion: 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. © 2016 Hellenic Society of Cardiology.