Pharmacological control of the mevalonate pathway: Effect on arterial smooth muscle cell proliferation

The mevalonate (MVA) pathway is involved in cell proliferation. We investigated drugs acting at different enzymatic steps on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy-3- methylglutaryl coenzyme A reductase (0.1-10 μM) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 μM MVA, 10 μM all-trans farnesol (F-OH) and 5 μM all-trans geranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 μM), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of cell proliferation was possible by all- trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 μM), a potent squalene synthase inhibitor, blocked cholesterol synthesis and slightly inhibited (21% decrease) SMC proliferation only at the highest tested concentration. NB-598 (1-10 μM), a potent squalene epoxidase inhibitor, blocked cholesterol synthesis without affecting SMC proliferation. Finally, the benzodiazepine peptidomimetic BZA-5B (10-100 μM), a specific inhibitor of protein farnesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was prevented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC proliferation was not affected by the closely related compound BZA-7B, which does not inhibit protein farnesyltransferase. Altogether, these findings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins, in the control of this cellular event.