PHARMACOLOGICAL CONTROL OF THE MEVALONATE PATHWAY - EFFECT ON ARTERIAL SMOOTH-MUSCLE CELL-PROLIFERATION

The mevalonate (MVB) pathway is involved in cell proliferation. We inv estigated drugs acting at different enzymatic steps on rat aorta smoot h muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy -3-methylglutaryl coenzyme A reductase (0.1-10 mu M) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 mu M MVA, 10 mu M all-trans famesol (F-OH) and 5 mu M all-trans ge ranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The sam e inhibitory effect was obtained with 6-fluoromevalonate (1-50 mu M), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of c ell proliferation was possible by all-trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 mu M), a potent squalene synthase in hibitor, blocked cholesterol synthesis and slightly inhibited (21% dec rease) SMC proliferation only at the highest tested concentration. NB- 598 (1-10 mu M), a potent squalene epoxidase inhibitor, blocked choles terol synthesis without affecting SMC proliferation. Finally, the benz odiazepine peptidomimetic BZA-5B (10-100 mu M), a specific inhibitor o f protein famesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was pre vented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC prol iferation was not affected by the closely related compound BZA-7B, whi ch does not inhibit protein farnesyltransferase. Altogether, these fin dings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites proba bly through farnesylated and geranylgeranylated proteins, in the contr ol of this cellular event.