Pleiotropic effects of statins in atherosclerosis and diabetes.
OBJECTIVE
To investigate the direct anti-atherosclerotic properties of statins.


METHODS
Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.


RESULTS
Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.


CONCLUSIONS
These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.
Bellosta
S
S
Institute of Pharmacological Sciences, University of Milan, Italy.
Ferri
N
N
Arnaboldi
L
L
Bernini
F
F
Paoletti
R
R
Corsini
A
A
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000517:prevention & control; D004705:Endocytosis / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000166:cytology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
D002788:Cholesterol Esters; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008074:Lipoproteins; D011725:Pyridines; D011758:Pyrroles; D000077340:Fluvastatin; D002784:Cholesterol; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin