Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

Atherosclerosis is a complex multifactorial process which results from an excessive inflammatory fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesions present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring in the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis - and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin (F) and simvastatin, but not pravastatin (P), dose-dependently decreased SMC migration and proliferation independently of their hypocholesterolemic properties. These cellular effects were prevented by the addition of mevalonate and by its derivatives famesol and geranylgeraniol confirming the specific role of isoprenoid metabolites, probably through a prenylated protein(s), in regulating cell proliferation. The inhibitory effect of F and simvastatin on cholesterol esterification induced by acetylated low-density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. The ability of F to interfere with arterial SMC proliferation at therapeutic concentrations (0.1 - 1 μM) prompted us to investigate the pharmacological activity of sera from 10 patients treated with 40 mg uid either F or P on the proliferation of cultured human SMC. F and P for 6 days in patients with type IIa hypercholesterolemia resulted in a similar decrease of LDL cholesterol. However, the addition of 15% whole-blood sera from patients treated with F to the culture medium caused an inhibition of cholesterol synthesis in SMC, that mirrored the pharmacokinetic profile of the drug. When SMC proliferation was investigated, a significant inhibition of cell growth (32%) decrease was detected with serum obtained 6 h after the last dose. No effect was observed when sera from patients treated with P were evaluated either on SMC proliferation or cholesterol biosynthesis. These results suggest that statins 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.