Effects of Simvastatin on Plasma Lipoproteins and Response to Arterial Injury in Wild-Type and Apolipoprotein-E-Deficient Mice

Objective: To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice. Methods and Results: Wild-type (WT) mice (n = 40) and hyperlipidemic apolipoprotein-E- deficient (apoE-/-) mice (n = 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9 ± 6.6 vs. 94.3 ± 17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE-/- mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17,090 ± 4,998 vs. 39,490 ± 16,190; p < 0.001). In apoE-/- mice, simvastatin caused a paradoxical increase in plasma cholesterol (1,094 ± 60.3 vs. 658 ± 66.8 mg/dl; p < 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39,490 ± 16,190 vs. 55,420 ± 22,590 mm₂; p < 0.01). Conclusions: (1) Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice; (2) hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3) simvastatin treatment of apoE-/- mice caused paradoxical hyperlipidemia and increased intimal hyperplasia.