Abstract
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-transfarnesol (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.
Footnotes
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Send reprint requests to: Dr. Alberto Corsini, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
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↵1 This research was partially supported by Consiglio Nazionale delle Ricerche (CNR)–Progetto Strategico “Ciclo Cellulare E Apoptosi.”.
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↵2 A visiting scientist under the terms of the U.S. (National Heart, Lung, and Blood Institute)-Italy bilateral agreement in the cardiovascular area.
- Abbreviations:
- MVA
- mevalonate
- HMG-CoA
- 3-hydroxy-3-methylglutaryl coenzyme A
- statin
- HMG-CoA reductase inhibitor
- PFTase
- protein farnesyltransferase
- PGGTase
- protein geranylgeranyltransferase
- F-OH
- farnesol
- GG-OH
- geranylgeraniol
- SMC
- smooth muscle cell
- MEM
- Minimum Essential Medium
- FCS
- fetal calf serum
- 6-Fmev
- 6-fluoromevalonolactone
- PP
- pyrophosphate
- Received July 25, 1996.
- Accepted February 6, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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