INHIBITION OF PROLIFERATION OF HUMAN SMOOTH-MUSCLE CELLS BY VARIOUS HMG-COA REDUCTASE INHIBITORS - COMPARISON WITH OTHER HUMAN CELL-TYPES

The effects of 6 HMG-CoA reductase inhibitors: pravastatin, lovastatin , simvastatin, atorvastatin, fluvastatin and cerivastatin were analyze d in cultured human smooth muscle cells, fibroblasts, endothelial cell s and myoblasts. In vascular smooth muscle cells, pravastatin was a mu ch weaker inhibitor of cholesterol synthesis than the 5 other drugs wh ich displayed equally strong inhibitory potency. The anti-proliferativ e effects of these 6 drugs were analyzed by measuring cell number and mitochondrial dehydrogenase activity (MTT assay) after 3 days of incub ation. IC25 values for inhibition of proliferation were very similar a mong the 4 cell types and were in the following order of magnitude: pr avastatin << lovastatin = simvastatin = atorvastatin = fluvastatin << cerivastatin. Only in the case of pravastatin was proliferation inhibi ted at lower concentration in smooth muscle cells than in the other ce ll types. Proliferation was also assessed by measuring DNA synthesis i n these cells. A 3 day-incubation with 1 mu M of pravastatin had no ef fect on this parameter in all 4 cell types. However, 1 mu M of simvast atin or lovastatin caused either an inhibition (in smooth muscle cells and endothelial cells) or stimulation (in fibroblasts) of this proces s. The effects of simvastatin on cell number, mitochondrial dehydrogen ase activity and DNA synthesis were counteracted by simultaneous meval onate addition. Simvastatin treatment was also associated with a chang e in the post-translational modification of the ras protein in smooth muscle cells, probably by inhibition of its farnesylation. Moreover, s imvastatin treatment blocked the PDGF and bFGF-induced DNA synthesis i n synchronized smooth muscle cells, whereas it does not affect the fet al calf serum-induced DNA synthesis in synchronized fibroblasts, sugge sting that simvastatin blacks various steps of the cell cycle and that this effect depends on the cell type and the growth signalling pathwa y activated. (C) 1997 Elsevier Science B.V.