title: Simvastatin reduces NF-kappaB activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet.
abstract: OBJECTIVE
  To study whether simvastatin reduces inflammation in atherosclerosis beyond its hypolipidemic effects.
  
  
  METHODS
  Twenty-four rabbits with induced femoral injury and on an atherogenic diet were randomized to normolipidemic diet (n=9), or to continue the atherogenic diet while receiving simvastatin 5 mg/kg/day (n=9) or no treatment (n=6) for 4 weeks.
  
  
  RESULTS
  As compared with no treatment, the normolipidemic diet significantly reduced lipid levels, while simvastatin produced nonsignificant reductions. In spite of this, NF-kappaB binding activity in peripheral mononuclear cells was reduced in the simvastatin group [2,958+/-5,123 arbitrary units (a.u.)] as compared with no treatment (49,267+/-20,084 a.u.; P<0.05) and normolipidemic groups (41,492+/-15,876 a.u.; P<0.05) (electrophoretic mobility shift assay). NF-kappaB activity in the atherosclerotic lesions was also reduced by simvastatin as compared to nontreated animals (4,108+/-3,264 vs. 8,696+/-2,305 nuclei/mm(2); P<0.05), while the normolipidemic diet induced only a nonsignificant diminution (P>0.05) (Southwestern histochemistry). Similarly, simvastatin decreased macrophage infiltration (4.6+/-12 vs. 19+/-12% of area staining positive; P<0.05) and the expression of interleukin-8 (24+/-12 vs. 63+/-21%; P<0.05) and metalloproteinase-3 (16+/-3 vs. 42+/-28%; P<0.05) (immunohistochemistry), while the reduction achieved by normolipidemic diet in all these parameters was again nonsignificant (P>0.05).
  
  
  CONCLUSIONS
  These findings suggest that simvastatin reduces inflammation in atherosclerotic plaques and in blood mononuclear cells more than expected for the lipid reduction achieved.
authors.affiliation: Vascular Research Unit, Fundación Jiménez Díaz and Universidad Autónoma, Madrid, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Hernández-Presa
authors.forename: Mónica
authors.initials: M
authors.lastname: Ortego
authors.forename: José
authors.initials: J
authors.lastname: Tuñón
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Sebastián
authors.initials: S
authors.lastname: Mas
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: César
authors.initials: C
authors.lastname: Aparicio
authors.forename: Luis
authors.initials: L
authors.lastname: Ortega
authors.forename: Juan
authors.initials: J
authors.lastname: Gómez-Gerique
authors.forename: Fernando
authors.initials: F
authors.lastname: Vivanco
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology* / Q000473:pathology; D004036:Diet, Atherogenic; D005263:Femoral Artery / Q000473:pathology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008262:Macrophage Activation; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D011897:Random Allocation; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000960:Hypolipidemic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D019821:Simvastatin; D019278:Matrix Metalloproteinase 3