PROLIFERATIVE EFFECT OF MEVALONATE METABOLITES OTHER THAN ISOPRENOIDS ON CULTURED VASCULAR SMOOTH-MUSCLE CELLS

1. Recent investigations revealed that isoprenoid compounds serve as key substances for cellular proliferation through post-translational modification. Previously we reported that tissues of spontaneously hypertensive rats (SHR) had a lower activity of isoprenoid biosynthesis when compared with the normotensive control rat (WKY). However, cultured vascular smooth muscle cells (VSMC) of SHR showed an enhanced growth rate. These findings led us to investigate further the effect of isoprenoid compounds on VSMC proliferation. 2. When the cells of WKY were stimulated with 5% fetal calf serum (FCS) in the presence of lovastatin, [H-3]-thymidine incorporation decreased in a dose-dependent manner and was completely inhibited at 30 mumol/L. Exogenously added mevalonate showed a protective effect against lovastatin (81% protection at 0.1 mumol/L). 3. Fluoromevalonate (Fmev), an inhibitor of mevalonate-PP decarboxylase which converts mevalonate-PP into isoprenoids, showed a dual inhibitory effect. DNA synthesis was partially inhibited at 0.01-1 mumol/L, however at 10 mumol/L there was no detectable inhibition. The inhibitory effect was again observed at concentrations over 10 mumol/L. 4. In the presence of lovastatin and Fmev to block both HMG CoA reductase and mevalonate-PP decarboxylase, exogenous mevalonate dose dependently stimulated [H-3]-thymidine incorporation induced by FCS. 5. These data suggest the positive effect of the initial mevalonate derivatives other than isoprenoid compounds on the proliferation of VSMC.