[The pharmacology of the statins: the evidence of a direct antiatherosclerotic action].
With the increasing knowledge on the pathogenesis of atherosclerosis, it appears that the prevention of cardiovascular disease in the future will involve, besides risk factor correction, direct pharmacological control of processes occurring in the arterial wall. Among them, a pivotal role is played by smooth muscle cell migration and proliferation that, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates (isoprenoids) of cholesterol synthesis are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently we provided evidence that fluvastatin, simvastatin, lovastatin, but not pravastatin, dose-dependently decrease smooth muscle cell migration and proliferation, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was completely prevented by the addition of mevalonate and partially (80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through prenylated proteins--in regulating these cellular events. The present results provide evidence that HMG-CoA reductase inhibitors interfere directly with processes involved in atherogenesis--beyond their effects on plasma lipids--partially through local inhibition of isoprenoid biosynthesis.
Raiteri
M
M
Istituto di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano.
Arnaboldi
L
L
Quarato
P
P
Paoletti
R
R
Fumagalli
R
R
Corsini
A
A
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077340:Fluvastatin; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017035:Pravastatin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin
D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin
Farmacologia delle statine: evidenze di un'azione antiaterosclerotica diretta.