Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells

Inflammation is involved in the genesis and rupture of atherosclerotic plaques. We assessed the effect of atorvastatin (ATV) on the expression of cyclooxygenase-2 (COX-2) and other proinflammatory molecules in a rabbit model of atherosclerosis. Fourteen animals underwent injury of femoral arteries and 2 weeks of atherogenic diet. Afterwards, they were randomized to receive either 5 mg/kg per day of ATV (n = 8) or no treatment (NT, n = 6) during 4 weeks. and were finally killed. ATV reduced lipid levels, neointimal size (0.13 (0.03-0.29) mm(2) vs 0.65 (0.14-1.81) mm(2), P=0.005) and the percentage of neointimal area positive for macrophages (1% (0-3) vs 19% (5-32). P = 0.001) COX-2 (32% (23-39) vs 60% (37-81) P = 0.019), interleukin-8 (IL-8) (23% (3-63) vs 63% (25-88) P = 0.015). and metalloproteinase-3 (19% (12-34) vs 42% (27-93), P = 0.010), without significant differences in COX-1 expression (immunohistochemistry). In situ hybridization confirmed a decreased expression of COX-2 mRNA (22% (5-40) vs 43% (34-59) P = 0.038). The activity of nuclear factor-kappaB, which controls many proinflammatory genes including COX-2. was reduced in atherosclerotic lesions (3538 (2663-5094) vs 8696 (5429-11 312)) positive nuclei per mm(2), P = 0.001) and circulating mononuclear cells (2966 vs 17 130 arbitrary units). In Cultured vascular smooth muscle cells, ATV reduced the expression of COX-2 mRNA induced by IL-1beta and TNF-alpha without affecting COX-1 expression. In conclusion, ATV, besides decreasing a number of inflammatory mediators in the atherosclerotic lesion, significantly downregulates COX-2 both in vivo and in vitro. These anti-inflammatory actions could partially account for the reduction of acute coronary events achieved by statins. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.