TY - JOUR
TI - The complementary effects of atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in apoE knockout mice
AU - Moustardas, P.
AU - Kadoglou, N.P.E.
AU - Katsimpoulas, M.
AU - Kapelouzou, A.
AU - Kostomitsopoulos, N.
AU - Karayannacos, P.E.
AU - Kostakis, A.
AU - Liapis, C.D.
JO - PLOS ONE
PY - 2014
VL - 9
TODO - 9
SP - null
PB - Public Library of Science
SN - null
TODO - 10.1371/journal.pone.0108240
TODO - apolipoprotein E;  atorvastatin;  cholesterol;  collagen;  elastin;  gelatinase A;  gelatinase B;  neutrophil collagenase;  stromelysin;  tissue inhibitor of metalloproteinase 1;  tissue inhibitor of metalloproteinase 2;  tissue inhibitor of metalloproteinase 3;  triacylglycerol;  apolipoprotein E;  atorvastatin;  cholesterol;  collagen;  elastin;  gelatinase A;  gelatinase B;  glucose blood level;  heptanoic acid derivative;  hydroxymethylglutaryl coenzyme A reductase inhibitor;  Mmp2 protein, mouse;  Mmp3 protein, mouse;  MMP8 protein, mouse;  Mmp9 protein, mouse;  neutrophil collagenase;  pyrrole derivative;  stromelysin;  Timp1 protein, mouse;  tissue inhibitor of metalloproteinase 1;  tissue inhibitor of metalloproteinase 2;  tissue inhibitor of metalloproteinase 3;  triacylglycerol, animal cell;  animal experiment;  animal model;  animal tissue;  aorta arch;  Article;  atherosclerotic plaque;  cholesterol blood level;  controlled study;  enzyme activity;  enzyme blood level;  exercise;  intervention study;  knockout mouse;  macrophage;  male;  mouse;  nonhuman;  protein localization;  smooth muscle fiber;  therapy effect;  triacylglycerol blood level;  animal;  atherosclerotic plaque;  blood;  clinical trial;  genetics;  glucose blood level;  lipid diet;  metabolism;  procedures;  randomization, Animals;  Apolipoproteins E;  Blood Glucose;  Cholesterol;  Collagen;  Diet, High-Fat;  Elastin;  Heptanoic Acids;  Hydroxymethylglutaryl-CoA Reductase Inhibitors;  Macrophages;  Male;  Matrix Metalloproteinase 2;  Matrix Metalloproteinase 3;  Matrix Metalloproteinase 8;  Matrix Metalloproteinase 9;  Mice;  Mice, Knockout;  Myocytes, Smooth Muscle;  Physical Conditioning, Animal;  Plaque, Atherosclerotic;  Pyrroles;  Random Allocation;  Tissue Inhibitor of Metalloproteinase-1;  Tissue Inhibitor of Metalloproteinase-2;  Tissue Inhibitor of Metalloproteinase-3;  Triglycerides
TODO - Aim: This study aimed to investigate the effects of combined atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in apolipoproteinE (apoE) knockout mice. Methods: Forty male, apoE-/- mice were fed a high-fat diet for 16 weeks. Thereafter, while maintained on high-fat diet, they were randomized into four (n = 10) groups for 8 additional weeks: Group CO: Control. Group AT: Atorvastatin treatment (10 mg/Kg/day). Group EX: Exercise-training on treadmill. Group AT+EX: Atorvastatin and simultaneous exercise training. At the study's end, plasma cholesterol levels, lipids and triglycerides were measured, along with the circulating concentrations of matrix-metalloproteinases (MMP-2,3,8,9) and their inhibitors (TIMP-1,2,3). Plaque area and the relative concentrations of collagen, elastin, macrophages, smooth muscle cells, MMP-2,3,8,9 and TIMP-1,2,3 within plaques were determined. Lastly, MMP activity was assessed in the aortic arch. Results: All intervention groups showed a lower degree of lumen stenosis, with atheromatous plaques containing more collagen and elastin. AT+EX group had less stenosis and more elastin compared to single intervention groups. MMP-3,-8 -9 and macrophage intra-plaque levels were reduced in all intervention groups. EX group had increased TIMP-1 levels within the lesions, while TIMP-2 was decreased in all intervention groups. The blood levels of the above molecules increased during atherosclerosis development, but they did not change after the therapeutic interventions in accordance to their intra-plaque levels. Conclusion: The two therapeutic strategies act with synergy regarding the extent of the lesions and lumen stenosis. They stabilize the plaque, increasing its content in elastin and collagen, by influencing the MMP/TIMP equilibrium, which is mainly associated with the macrophage amount. While the increased MMP-2,-3,-8 -9, as well as TIMP-1 and TIMP-2 circulating levels are markers of atherosclerosis, they are not correlated with their corresponding concentrations within the lesions after the therapeutic interventions, and cannot serve as markers for the disease development/amelioration. © 2014 Moustardas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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