title: The complementary effects of atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in ApoE knockout mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Petros
authors.initials: P
authors.lastname: Moustardas
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Nikolaos P E
authors.initials: NP
authors.lastname: Kadoglou
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Michalis
authors.initials: M
authors.lastname: Katsimpoulas
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Alkistis
authors.initials: A
authors.lastname: Kapelouzou
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kostomitsopoulos
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Panayotis E
authors.initials: PE
authors.lastname: Karayannacos
authors.affiliation: Center for Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Alkiviadis
authors.initials: A
authors.lastname: Kostakis
authors.affiliation: Department of Vascular Surgery, «Attikon» Hospital, Medical School, University of Athens, Athens, Greece.
authors.forename: Christos D
authors.initials: CD
authors.lastname: Liapis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D000069059:Atorvastatin; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004549:Elastin / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020784:Matrix Metalloproteinase 8 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle; D010805:Physical Conditioning, Animal / Q000379:methods*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000097:blood; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D014280:Triglycerides; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D004549:Elastin; D002784:Cholesterol; D000069059:Atorvastatin; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse