Nitric oxide enhances the anti-inflammatory and anti-atherogenic activity of atorvastatin in a mouse model of accelerated atherosclerosis

The 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. 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 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 the following parameters: 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 in the aorta (dichlorofluorescein fluorescence intensity per milligram 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 interleukin-6 (atorvastatin 34.3 6.8 pg/mL; NCX 6560 17.7 14.4 pg/mL; P 0.05); and matrix metalloproteinase 2 in the arterial wall (atorvastatin 55.2 1.9 ng/g of proteins; NCX 6560 45.8 2.6 ng/g of proteins; P 0.05). In conditions of severe endothelial dysfunction, systemic peroxidation and inflammation, and accelerated atherosclerosis, atorvastatin, even at high doses, displays suboptimal anti-atherogenic and anti-inflammatory effects, while the addition of a NO-donating property confers enhanced anti-atherogenic and anti-inflammatory effects.