Inhibition of isoprenoid biosynthesis and arterial smooth-muscle cell proliferation.
Recently, we provided in vitro and in vivo evidence that several vastatins with different potencies decrease arterial smooth-muscle cell (SMC) proliferation independently of their hypocholesterolemic properties. In this study, the in vivo dose-dependent antiproliferative activity of fluvastatin on neointimal formation induced by the insertion of a collar around one carotid artery was investigated in normocholesterolemic rabbits (five animals per treatment group). Intraperitoneal fluvastatin treatment progressively inhibited intimal to medial tissue ratios (I/M) by 5, 48, and 64% versus controls at doses of 3, 5, or 10 mg/kg/day, respectively. Local arterial delivery by an Alzet pump of mevalonate (8 mg/kg/day) at the site of collar placement fully prevented a fluvastatin (5 mg/kg/day) inhibitory effect on both I/M and SMC proliferation, as assessed by direct incorporation of bromodeoxyuridine (BrdU) into replicating DNA. The results suggest that vastatins exert a direct antiproliferative effect on intimal myocytes beyond their effects on plasma lipids, probably through local inhibition of isoprenoid biosynthesis.
Soma
M R
MR
Institute of Pharmacological Sciences, Milan, Italy.
Parolini
C
C
Donetti
E
E
Fumagalli
R
R
Paoletti
R
R
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D000077340:Fluvastatin; D007091:Image Processing, Computer-Assisted; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D007274:Injections, Intraperitoneal; D008148:Lovastatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D019821:Simvastatin
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D008148:Lovastatin; D019821:Simvastatin; D001973:Bromodeoxyuridine; D017035:Pravastatin; D008798:Mevalonic Acid