289 ROSUVASTATIN REDUCES ATHEROSCLEROSIS INDEPENDENTLY OF ITS CHOLESTEROL-LOWERING EFFECT IN APOE3*LEIDEN TRANSGENIC MICE L.M. Havekes, W. Van Duyvenvoorde, M.C.E. Maas, H. Van Der Boom, C.M. Van Den Hoogen, J.J. Emeis, H.M.G. Princen TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands We investigated the effect of a new HMG-CoA reductase inhibitor, rosuvastatin (Crestor), on the development of aortic atherosclerosis in the apoE3*Leiden mouse, an established rodent model sensitive to the effects of anti-hypercholesterolaemic and anti-atherosclerotic drugs. Hypercho- lesterolaemia and atherosclerosis were induced by addition of 1% cholesterol to the diet (HC group). A treatment group received the same diet containing 0.005% w/w rosuvastatin (HC+R). An additional group received lower amounts of cholesterol in the diet (LC) to parallel the plasma cholesterol levels of the HC+R group, but without rosuvastatin treatment. After 24 weeks treatment, rosuvastatin significantly reduced plasma cholesterol and triglyceride levels by 25% and 45%, respectively (p<0.01), compared to the HC control group. Overall plasma cholesterol exposure in the HC+R and cholesterol-matched LC groups was comparable (approximately 300mM/wk), and significantly lower than the HC group (410 mM/wk, p<0.001). There was significant reduction in progression of the aortic root total lesion area (-60%, p<0.001) and average lesion size (-55%, p<0.001) in the LC group compared to the HC group. Compared to the cholesterol-matched LC group, the HC+R group showed significant additional reduction in total lesion area (-81%, p<0.001) and average lesion size (-65%, p<0.001). Similar changes were seen in the aortic arch regions. Compared to the HC and LC groups, in the HC+R group serum amyloid A was reduced by 45% and 30%, respectively (p<0.001). Thus, rosuvastatin elicited an additional significant reduction in the progression of aortic atherosclerosis independently of its cholesterol lowering activity and possibly via an anti-inflammatory action.