Simvastatin and Losartan Differentially and Synergistically Inhibit Atherosclerosis in Apolipoprotein Mice

Background and Objectives: Since statins and angiotensin receptor blockers are a frequently prescribed combination in patients with atherosclerotic cardiovascular diseases, we tested the interactive effects of simvastatin and losartan on atherosclerosis in apolipoprotein E $(apoE)^{-/-}$ mice. Materials and Methods: Apolipoprotein $E^{-/-}$ mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks, with and without simvastatin (40 mg/kg) and/or losartan (20 mg/kg). The mice were divided into 5 groups and were fed as follows: regular chow (control diet, n=5), HFHC diet (n=6), HFHC diet with losartan (n=6), HFHC diet with simvastatin (n=6), and HFHC diet with both losartan and simvastatin (n=6). Results: Losartan treatment in $apoE^{-/-}$ mice significantly decreased atherosclerotic lesion areas in whole aortic strips stained with Oil Red O. The plaque area measured at the aortic sinus level was reduced significantly by 17% (HFHC; $346830.9{\pm}52915.8\;{\mu}m^2$ vs. HFHC plus losartan; $255965.3{\pm}74057.7\;{\mu}m^2$, p<0.05) in the losartan-treated group. Simvastatin and simvastatin plus losartan treatments reduced macrophage infiltration into lesions by 33% (HFHC; $183575.6{\pm}43211.2\;{\mu}m^2$ vs. HFHC plus simvastatin; $120556.0{\pm}39282.8\;{\mu}m^2$, p<0.05) and 44% (HFHC; $183575.6{\pm}43211.2\;{\mu}m^2$ vs. HFHC plus simvastatin and losartan; $103229.0{\pm}8473.3\;{\mu}m^2$, p<0.001, respectively). In mice fed the HFHC diet alone, the smooth muscle cell layer in the aortic media was almost undetectable. In mice co-treated with losartan and simvastatin, the smooth muscle layer was more than 60% preserved (p<0.05). Given alone, losartan showed a slightly stronger effect than simvastatin; however, treatment with losartan plus simvastatin induced a greater inhibitory effect on atherosclerosis than either drug given alone. Serum lipid profiles did not differ significantly among the groups. Conclusion: Losartan displayed anti-atherosclerotic effects in $apoE^{-/-}$ mice that were equivalent to or greater than the effects of simvastatin. Combined treatment with these drugs had greater effect than either drug alone.