Simvastatin reduces NF-kappaB activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet.
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.
Hernández-Presa
Miguel Angel
MA
Vascular Research Unit, Fundación Jiménez Díaz and Universidad Autónoma, Madrid, Spain.
Ortego
Mónica
M
Tuñón
José
J
Martín-Ventura
José Luis
JL
Mas
Sebastián
S
Blanco-Colio
Luis Miguel
LM
Aparicio
César
C
Ortega
Luis
L
Gómez-Gerique
Juan
J
Vivanco
Fernando
F
Egido
Jesús
J
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*
D000960:Hypolipidemic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D019821:Simvastatin; D019278:Matrix Metalloproteinase 3