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Cardiovascular Research 2003 57(1):168-177; doi:10.1016/S0008-6363(02)00619-3
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Simvastatin reduces NF-{kappa}B activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet

Miguel Angel Hernández-Presaa, Mónica Ortegoa, José Tuñónb, José Luis Martín-Venturaa, Sebastián Masc, Luis Miguel Blanco-Colioa, César Apariciod, Luis Ortegae, Juan Gómez-Geriquef, Fernando Vivancoc and Jesús Egidoa,*

aVascular Research Unit, Fundación Jiménez Díaz and Universidad Autónoma, Madrid, Spain
bDepartment of Cardiology, Fundación Jiménez Díaz and Universidad Autónoma, Madrid, Spain
cDepartment of Immunology, Fundación Jiménez Díaz and Universidad Complutense, Madrid, Spain
dDepartment of Vascular Surgery, Fundación Jiménez Díaz, Madrid, Spain
eDepartment of Pathology, Hospital Clínico San Carlos, Madrid, Spain
fDepartment of Biochemistry, Fundación Jiménez Díaz, Madrid, Spain

jegido{at}fjd.es

* Corresponding author. Vascular Research Unit, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040 Madrid, Spain. Tel.: +34-91-550-4800x3168; fax: +34-91-549-8075.

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-{kappa}B 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-{kappa}B 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/mm2; P<0.05), while the normolipidemic diet induced only a nonsignificant diminution (P0.05) (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 (P0.05). Conclusions: These findings suggest that simvastatin reduces inflammation in atherosclerotic plaques and in blood mononuclear cells more than expected for the lipid reduction achieved.

KEYWORDS Atherosclerosis; Cholesterol; Gene expression; Infection/inflammation; Macrophages; Statins


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