Effects of a competitive inhibitor (mevinolin) of 3-hydroxy-3-methylglutaryl coenzyme A reductase on human and bovine endothelial cells, fibroblasts and smooth muscle cells in vitro.

Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, is a potent inhibitor of cholesterol synthesis. We have tested the effects of mevinolin on cell replication (3H-thymidine incorporation), prostacyclin production (6-keto-PGF1 alpha) and cell death (51Cr release) in cell cultures (human umbilical vein endothelial cells, bovine endothelial cells, human fibroblasts and bovine smooth muscle cells). Mevinolin concentrations ranging from 0.05 mumol/l (reported therapeutic concentration) to 20 mumol/l were used. In human endothelial cells the replication was reduced by 11% at a concentration of 2.0 mumol/l (P less than 0.01). In fibroblasts and smooth muscle cells the reduction was significant already at 0.1 mumol/l (10%, P less than 0.01). The prostacyclin production was reduced in endothelial cells at 1.0 mumol/l (19%, P less than 0.01) and in smooth muscle cells at 2.0 mumol/l (15%, P less than 0.05). At 20 mumol/l both cell replication and prostacyclin production was markedly reduced by about 40% in all cell types. No effects on 51Cr release or trypan blue staining was seen at any concentration. It is concluded that mevinolin has an effect on DNA synthesis and prostacyclin production on the tested cell types in vitro. These effects were, however, observed only at concentrations higher than those recommended for therapeutical use.