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Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury

^a Division of Cardiology, University Federico II, Naples, Italy

View larger version (15K): [in a new window]   Figure 1 Effects of simvastatin (2 µmol/liter) on the growth inhibition of rat VSMCs. In treated rats simvastatin (open boxes) induced a significant inhibition of VSMC proliferation as compared with control rats (solid diamonds). This effect was completely reversed by addition of mevalonate (100 µmol/liter) to the medium (open circles), but it was not affected by addition of 25-OH-cholesterol (100 µg/ml) (solid triangles). *p < 0.01 vs. control rats and simvastatin plus mevalonate treatment.

View larger version (87K): [in a new window]   Figure 2 Representative histologic sections stained with hematoxylin-eosin of the common carotid arteries from (a) a control rat subjected to only balloon injury; (b) a rat treated with 0.04 mg/kg simvastatin; (c) a rat treated with 4 mg/kg simvastatin; (d) a rat treated with 16 mg/kg simvastatin; (e) a rat treated with 40 mg/kg simvastatin; and (f) a rat treated with 40 mg/kg simvastatin plus local administration of mevalonate (10 mmol/liter).

View larger version (23K): [in a new window]   Figure 3 Neointima-media (N/M) ratio and neointimal cross-sectional area (neointima) of common carotid arteries from rats subjected to only balloon injury (solid bars), rats treated with 40 mg/kg per day of simvastatin (open bars) and rats treated with simvastatin at the highest dose and local administration of mevalonate (striped bars). *p < 0.01 vs. control group and mevalonate group.

View larger version (12K): [in a new window]   Figure 4 Percent changes of plasma cholesterol levels (solid circles) and neointima-media ratio (solid squares) after balloon injury in rats treated with different simvastatin doses. It is evident that simvastatin reduced the cholesterol levels by 20%, independent of the simvastatin dose used. In contrast, at the same level of cholesterol reduction, the effect on the neointima-media ratio after balloon dilation was more pronounced after increasing the simvastatin doses. This finding, together with the in vitro data, strongly suggests that the beneficial effect of simvastatin on the vascular response to injury is not dependent only on cholesterol level reduction. *p < 0.05 vs. control group. #p < 0.001 vs. control group and treatment with 0.04, 4 and 16 mg/kg simvastatin.

View larger version (9K): [in a new window]   Figure 5 Neointima-media (N/M) ratio and neointimal cross-sectional area (neointima) of common carotid arteries from rats subjected to only NIR 7-cell stent implantation (solid bars); rats treated with 40 mg/kg per day simvastatin 14 days before and 21 days after stent implantation (open bars). *p < 0.05 vs. control group.

View larger version (39K): [in a new window]   Figure 6 Representative histologic sections stained with hematoxylin-eosin of arteries from (a) a control rat’s carotid artery after stent deployment; (b) same artery after stent implantation in a rat treated with 40 mg/kg per day simvastatin.