Nitric oxide enhances the anti-inflammatory and anti-atherogenic activity of atorvastatin in a mouse model of accelerated atherosclerosis
Aims Aim of the present study was to assess whether the addition of a nitric oxide (NO)-donating moiety to atorvastatin enhances anti-inflammatory and anti-atherogenic effects in an animal model of endothelial dysfunction, systemic peroxidation and inflammation, and accelerated atherosclerosis.
Methods and Results Low-density-lipoprotein-receptor (LDLR)-/- mice kept on a high fat diet (HFD) for 16 weeks underwent photochemical-injury to the femoral artery with the local production of oxygen radicals. HFD markedly enhanced cholesterol, inflammatory biomarkers in plasma and in the femoral arterial wall, and enhanced atherosclerotic lesions in the aortic arch; inflammation and atherosclerosis were further increased by photochemically-generated oxygen radicals.
Treatment with the NO-donating atorvastatin NCX 6560 (11.7 mg/kg), was significantly more effective than atorvastatin (10 mg/kg) in reducing: lipid-rich lesions in the aortic arch (surface covered: atorvastatin=24±5%; NCX 6560=14.7±3.9%, p<0.05), the production of radical oxygen species (ROS) in aortas (DCF fluorescence intensity/mg of protein: atorvastatin=2419±136.7; NCX 6560=1766±161.2, p<0.05), femoral artery intima/media thickness (atorvastatin=1.2±0.11; NCX 6560=0.3±0.14, p<0.05), circulating IL-6 (atorvastatin=34.3±6.8 pg/ml; NCX 6560=17.7±14.4 pg/ml, p<0.05) and matrix-metalloproteinase (MMP)-2 in the arterial wall (atorvastatin=55.2±1.9 ng/µg of proteins; NCX 6560=45.8±2.6 ng/µg of proteins, p<0.05).
Conclusions In conditions of severe endothelial dysfunction, systemic peroxidation and inflammation and accelerated atherosclerosis atorvastatin, even at high doses, displays sub-optimal antiatherogenic and antiinflammatory effects while the addition of a NO-donating property confers enhanced and anti-atherogenic and antiinflammatory effects.