The role of mevalonic acid (MVA) and its products (isoprenoids) in cell proliferation prompted us to investigate the effect of drugs affecting diverse enzymatic steps of the MVA pathway on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of HMG-CoA reductase (statins) decreased SMC proliferation in a dose-dependent manner. The inhibitory effect induced by simvastatin 3.5 microM (70% +/- 3.8 decrease) was prevented by addition of 100 microM MVA, (100% +/- 2.3), 10 microM farnesol (F-OH) (85% +/- 1.2) and 5 microM of all-trans geranylgeraniol (GG-OH) (precursor of prenylated proteins) (81% +/- 1.1), but not by 2-cis GG-OH (precursor of dolichols), squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-PP decarboxylase. Squalestatin 1 (1-25 microM) and NB-598 (1-10 microM), potent squalene synthase and epoxidase inhibitors, respectively, caused a complete inhibition of cholesterol synthesis without affecting SMC proliferation. Finally, BZA-5B (10-50 microM) a specific inhibitor of protein farnesyl tranferase (PFTase), inhibited SMC proliferation in a dose- (10-50 microM) and time-dependent manner, reaching 52% +/- 6.3 inhibition after 9 days, in the presence of 50 microM BZA-5B, without affecting cholesterol synthesis. This effect was partially prevented by mevalonate (76% +/- 3.2) and GG-OH (87% +/- 7.3) but not by F-OH. On the other hand, SMC proliferation was not affected by the closely related compound BZA-7B (93% +/- 4), which does not inhibit PFTase. Taken together, these findings support the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins in cell proliferation.
Controle pharmacologique de la voie de biosynthese du mevalonate: effet sur la proliferation de cellules musculaires lisses arterielles / A. Corsini, L. Arnaboldi, P. Quarato, N. Ferri, A. Granata, R. Fumagalli, R. Paoletti. - In: COMPTES RENDUS DES SEANCES DE LA SOCIETE DE BIOLOGIE ET DE SES FILIALES. - ISSN 0037-9026. - 191:2(1997), pp. 169-194.
|Titolo:||Controle pharmacologique de la voie de biosynthese du mevalonate: effet sur la proliferation de cellules musculaires lisses arterielles|
CORSINI, ALBERTO (Primo)
ARNABOLDI, LORENZO (Secondo)
PAOLETTI, RODOLFO (Ultimo)
|Parole Chiave:||Animals ; Tricarboxylic Acids ; Dose-Response Relationship, Drug ; Aorta ; Mevalonic Acid ; Enzyme Inhibitors ; Thiophenes ; Cholesterol; Bicyclo Compounds, Heterocyclic ; Farnesyl-Diphosphate Farnesyltransferase ; Benzylamines ; Rats ; Rats, Sprague-Dawley ; Benzodiazepines ; Muscle, Smooth, Vascular ; Oligopeptides ; Male ; Cell Division|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1997|
|Appare nelle tipologie:||01 - Articolo su periodico|