title: Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice.
abstract: OBJECTIVE
  To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect.
  
  
  RESULTS
  ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP transgenic mice.
  
  
  CONCLUSIONS
  Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect.
authors.affiliation: Gaubius Laboratory, TNO-Prevention and Health, Leiden, The Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.forename: Erik H
authors.initials: EH
authors.lastname: Offerman
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.forename: Sjef J
authors.initials: SJ
authors.lastname: Emeis
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000473:pathology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000178:diet therapy* / Q000188:drug therapy* / Q000473:pathology; D000069059:Atorvastatin; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004036:Diet, Atherogenic; D004334:Drug Administration Schedule; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000178:diet therapy / Q000188:drug therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000685:Serum Amyloid A Protein / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; D000685:Serum Amyloid A Protein; C052720:apolipoprotein E3 (Leidein); D002097:C-Reactive Protein; D002784:Cholesterol; D000069059:Atorvastatin