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 B 16,190 vs. 55,420 B 22,590 mm(2); 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. Copyright (C) 2004 S. Karger AG, Basel.