VascularThe Effect of Six Different Statins on the Proliferation, Migration, and Invasion of Human Smooth Muscle Cells
Introduction
The treatment of peripheral vascular disease, although greatly improved over recent decades by surgical and endovascular procedures, remains limited by intimal hyperplasia (IH). IH leads to focal stenoses that threaten the patency of up to 35% of lower limb vein bypass grafts [1]. IH is thought to result from abnormal activation of smooth muscles cells after vessel manipulation. Normally, smooth muscle cells (SMCs) reside in the vessel wall media in a quiescent differentiated and contractile state. However, SMCs seem to be easily activated after injury and this activation of SMCs is associated with a shift from a contractile to a synthetic phenotype, itself leading to SMC proliferation, migration, and synthesis of extracellular matrix [2].
Although several pharmacological approaches have been shown to reduce IH in animal models, these results have not been reproduced in human clinical trials. Statins are a class of drugs used to reduce plasma cholesterol levels in patients with hypercholesterolemia [3]. Large clinical trials have shown that the beneficial effects of statins in patients with atherosclerotic disease are attributable to the inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis [4, 5, 6]. Laufs and colleagues [7] have shown that some of the effects of HMG-CoA reductase inhibitors on SMC are independent of their effects on plasma cholesterol levels, probably through inhibition of isoprenoid synthesis that is a precursor of prenylated proteins. Corsini and colleagues [8] have shown that statins can decrease rat aortic SMC migration and proliferation by interfering with signaling pathways requiring prenylated proteins. The effect of simvastastin on IH development in human saphenous vein organ culture has previously been reported by Porter et al. [9] who found that simvastatin reduced IH and that simvastatin inhibited isolated human SMC proliferation and migration. The purpose of the present study was to investigate whether the beneficial effects of HMG-CoA reductase inhibitors on human SMC proliferation is a class effect or is confined to specific statins.
Section snippets
SMC Isolation and Culture
Human saphenous SMCs were prepared using an explant technique. Vein segments were chopped into small fragments (approximately 1 mm3) within a 2-ml volume of RPMI medium supplemented with 10% fetal calf serum (FCS). The vein fragments together with the medium were transferred to 25 cm2 tissue culture flasks and maintained at 37°C in a humidified incubator in 5% CO2 in air. After 1 to 2 weeks SMCs were seen to migrate out from the explants, and at 4 to 5 weeks cells were passaged into 80 cm2
Effects of Statins on SMC Proliferation
The results of the proliferation studies are shown in Fig. 1. To calculate the effect of the statins on proliferation the area under the curve (AUC) for each experiment was calculated and the AUCs for each statin expressed as a percentage of the 10% FCS control. The median AUC for atorvastatin was 61% of control, cerivastatin 58%, fluvastatin 33%, lovastatin 60%, pravastatin 72%, and simvastatin 57%. These percentage AUCs were all significantly lower than control (P = 0.03). The percent
Discussion
Our results show that all six statins significantly reduce human vascular SMC proliferation, migration, and invasion. Although all of the statins were equally effective at reducing migration and invasion, fluvastatin appeared particularly effective at reducing SMC proliferation. We have not been able to find any other comparisons of the effects of different statins on human venous SMC proliferation. However, Nègre-Aminou et al. [10] did compare the effect of the same six statins on human
Acknowledgments
We are grateful to Dawn Croston for technical assistance and expertise.
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