Effect of the new HMG-CoA reductase inhibitor cerivastatin (BAY W 6228)on migration, proliferation and cholesterol synthesis in arterial myocytes.
The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC50 values of 2.7 microM and 0.5 microM, respectively. Among the tested statins BAY W 6228 resulted to be the most potent inhibitor of cholesterol synthesis and cell proliferation. Conditions producing 80-90% inhibition of cholesterol synthesis correlate with approximately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitro inhibition of cell migration and proliferation induced by BAY W 6228 (80% decrease) was completely prevented by the addition of mevalonate and partially prevented (60-80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in regulating these cellular events. The present results provide evidence that BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis.
Corsini
A
A
Institute of Pharmacological Sciences, University of Milan, Italy.
Arnaboldi
L
L
Raiteri
M
M
Quarato
P
P
Faggiotto
A
A
Paoletti
R
R
Fumagalli
R
R
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D002784:Cholesterol; C086276:cerivastatin