Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types

• Published in: Biochimica et biophysica acta 1997-04, Vol.1345 (3), p.259-268
• Main Authors: Nègre-Aminou, Pascale, van Vliet, Arlene K, van Erck, Monique, van Thiel, G.Christa F, van Leeuwen, Rick E.W, Cohen, Louis H
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - pharmacology; Cell Division - drug effects; Cells, Cultured; Cholesterol - biosynthesis; DNA - biosynthesis; DNA synthesis; Endothelial cell; Enzyme Inhibitors - pharmacology; Fibroblast; Human; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin - analogs & derivatives; Lovastatin - antagonists & inhibitors; Lovastatin - pharmacology; Mevalonate; Muscle, Smooth, Vascular - drug effects; Myoblast; Pravastatin - pharmacology; ras; ras Proteins - metabolism; Simvastatin; Smooth muscle cell; Vastatin
• ISSN: 0005-2760; 0006-3002; 1879-145X
• DOI: 10.1016/S0005-2760(96)00184-1

The effects of 6 HMG-CoA reductase inhibitors: pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin were analyzed in cultured human smooth muscle cells, fibroblasts, endothelial cells and myoblasts. In vascular smooth muscle cells, pravastatin was a much weaker inhibitor of cholesterol synthesis than the 5 other drugs which displayed equally strong inhibitory potency. The anti-proliferative effects of these 6 drugs were analyzed by measuring cell number and mitochondrial dehydrogenase activity (MTT assay) after 3 days of incubation. IC 25 values for inhibition of proliferation were very similar among the 4 cell types and were in the following order of magnitude: pravastatin≪lovastatin=simvastatin=atorvastatin=fluvastatin≪cerivastatin. Only in the case of pravastatin was proliferation inhibited at lower concentration in smooth muscle cells than in the other cell types. Proliferation was also assessed by measuring DNA synthesis in these cells. A 3 day-incubation with 1 μM of pravastatin had no effect on this parameter in all 4 cell types. However, 1 μM of simvastatin or lovastatin caused either an inhibition (in smooth muscle cells and endothelial cells) or stimulation (in fibroblasts) of this process. The effects of simvastatin on cell number, mitochondrial dehydrogenase activity and DNA synthesis were counteracted by simultaneous mevalonate addition. Simvastatin treatment was also associated with a change in the post-translational modification of the ras protein in smooth muscle cells, probably by inhibition of its farnesylation. Moreover, simvastatin treatment blocked the PDGF and bFGF-induced DNA synthesis in synchronized smooth muscle cells, whereas it does not affect the fetal calf serum-induced DNA synthesis in synchronized fibroblasts, suggesting that simvastatin blocks various steps of the cell cycle and that this effect depends on the cell type and the growth signalling pathway activated. © 1997 Elsevier Science B.V. All rights reserved.