Pleiotropic effects of statins in atherosclerosis and diabetes

OBJECTIVE - To investigate the direct anti-atherosclerotic properties of st atins. RESEARCH DESIGN AND METHODS - Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been inve stigated. We studied the ability of statins to modulate modified LDL-induce d cholesterol esterification, metalloproteinase secretion by macrophages, a nd arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the anti proliferative effect of sera from statin-treated patients has been confirme d in a cell culture system. RESULTS - Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivasta tin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC ) migration and proliferation. Moreover, statins are able to reduce cholest erol accumulation in macrophages in vitro by blocking cholesterol esterific ation and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trails farnesol and all-trans geranylgeraniol, confirm ing the specific role of isoprenoid metabolites (probably through prenylate d protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of prolife rating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their abil ity 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 coenzym e A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effe ct in the arterial wall, beyond their effects on plasma lipids that could t ranslate into a more significant prevention of cardiovascular disease. Thes e findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients-a population with a higher absolut e risk of recurrent cardiovascular events.