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EXPERIMENTAL STUDIES

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

Manuscript received March 19, 1999; revised manuscript received July 30, 1999, accepted October 5, 1999.

Reprint requests and correspondence: Dr. Ciro Indolfi, Laboratory of Interventional Cardiology, Division of Cardiology, University Federico II, Via Pansini, 5, 80131 Napoli, Italy
Indolfi{at}unina.it

OBJECTIVES

We sought to evaluate the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on vascular smooth muscle cell (VSMC) proliferation in vitro and neointimal formation in vivo after vascular injury.

BACKGROUND

Neointimal hyperplasia after vascular injury is responsible for restenosis after arterial stenting, whereas arterial remodeling and neointimal formation are the causes of restenosis after percutaneous transluminal coronary angioplasty.

METHODS

We assessed the effect of simvastatin on in vitro VSMC proliferation. To study the effects of simvastatin in vivo, balloon injury and stent deployment were performed in the common carotid artery of rats. Neointimal area was measured two weeks later in the balloon injury model and three weeks after stent deployment.

RESULTS

Simvastatin markedly inhibits VSMC proliferation in vitro. In vivo, simvastatin reduced, in a dose-dependent manner, the neointimal area and the neointima-media ratio after balloon injury from 0.266 ± 0.015 mm² to 0.080 ± 0.026 mm² and from 1.271 ± 0.074 to 0.436 ± 0.158 (p < 0.001 vs. control rats) at the highest dose. Simvastatin also significantly reduced the neointimal formation and the neointima-media ratio after stenting from 0.508 ± 0.035 mm² to 0.362 ± 0.047 mm² (p < 0.05 vs. control rats) and from 2.000 ± 0.136 to 1.374 ± 0.180 (p < 0.05 vs. control rats). The vessel thrombosis rate after stent deployment was 30% in the control group and 11.1% in the treated group (p = NS). Moreover, the systemic administration of simvastatin did not affect hepatic and renal functions, blood pressure or heart rate.

CONCLUSIONS

Simvastatin potently inhibits VSMC proliferation in vitro and reduces neointimal formation in a rat model of vascular injury.

Abbreviations and Acronyms   DMEM = Dulbecco’s modified Eagles medium   FCS = fetal calf serum   GTPase = glutamyl transpeptidase   HMG-CoA = hydroxymethylglutaryl coenzyme A   MAPKK = mitogen-activated protein kinase kinase   MVA = mevalonic acid   PBS = phosphate-buffered saline   PTCA = percutaneous transluminal coronary angioplasty   VSMC = vascular smooth muscle cell

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