title: Olmesartan and pravastatin additively reduce development of atherosclerosis in APOE*3Leiden transgenic mice.
abstract: OBJECTIVE
  This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice.
  
  
  RESULTS
  Four groups of 15 mice received an atherogenic diet alone (plasma cholesterol 17.4 +/- 2.7 mmol/l) or supplemented with either 0.008% (w/w) olmesartan (9.3 mg/kg per day) (plasma cholesterol 16.4 +/- 3.9 mmol/l), 0.03% (w/w) pravastatin (35 mg/kg per day) (plasma cholesterol 14.6 +/- 2.6 mmol/l), or the combination of both (plasma cholesterol 14.5 +/- 2.9 mmol/l) for 6 months. Treatment with olmesartan or pravastatin reduced the development of atherosclerosis as compared to the control group (-46 and -39%, respectively). Pravastatin also reduced the severity of the lesions. As compared to control the combination of both treatments almost fully prevented atherosclerosis (-91%, P < 0.001) and strongly reduced lesion number (-69%), lesion severity (-79%), number of macrophages (-89%) and T lymphocytes (-86%) per cross-section. Treatment with olmesartan alone and in combination with pravastatin inhibited the adhesion of monocytes to the vessel wall (-22%; P < 0.05 and -25%; P < 0.01, respectively), and reduced the relative quantity of macrophages in the lesions (-38%; P < 0.05 and -26%; NS, respectively) as compared to control.
  
  
  CONCLUSIONS
  Olmesartan reduced atherosclerosis development mainly by decreasing monocyte adhesion and the relative amount of macrophages, whereas pravastatin inhibited the progression of atherosclerosis to more advanced lesions, reflecting different anti-atherosclerotic modes of action of the two drugs. Combination therapy with olmesartan and pravastatin additively reduced atherosclerosis development, resulting in less and less severe lesions.
authors.affiliation: Department of Cardiology, Leiden University Medical Centre, The Netherlands.
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004357:Drug Synergism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007093:Imidazoles / Q000008:administration & dosage*; D007249:Inflammation / Q000517:prevention & control; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D017035:Pravastatin / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D053318:Apolipoprotein E3; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D008055:Lipids; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D013777:Tetrazoles; C052720:apolipoprotein E3 (Leidein); C437965:olmesartan; D003094:Collagen; D017035:Pravastatin