Statin-induced vascular smooth muscle cell apoptosis: a possible role in the prevention of restenosis?

Growing evidence suggests that statins are more than simple lipid-lowering drugs. The so called pleiotropic effects of statins include multiple actions on cells of the vasculature. A large number of studies have confirmed that these compounds exert beneficial effects by mechanisms unrelated to cholesterol metabolism. For example, statins have been shown to inhibit the migration and proliferation of vascular smooth muscle cells (VSMC), and to induce apoptosis in this cell type. It is not yet clear if the induction of apoptosis in VSMC by statins is beneficial or detrimental. In the context of post-angioplasty restenosis, recurrent plaque growth after intervention, the inhibition of neointimal proliferation as well as a reduction of neointimal cell numbers by apoptosis is appealing. Multiple animal studies and clinical trials have therefore been undertaken to investigate effects of statin treatment on the development of restenosis, with very controversial results. Conversely, in advanced atherosclerotic lesions VSMC in the intima may stabilize the plaque and prevent plaque rupture by synthesizing collagen. VSMC in media adjacent to plaque areas or restenotic lesions should not be exposed to apoptosis promoting agents. In this context, recent evidence suggests that pravastatin protects such lesions by inhibiting inflammation and macrophage activation Our recent findings together with observations from other groups suggest that neointima cells are more sensitive to the induction of apoptosis than media VSMC. Importantly, statins were found to preferentially induce apoptosis in neointimal VSMC in our study. The purpose of the present review is to summarize statin effects on proliferation and apoptosis in VSMC in vitro and in vivo. Furthermore, the development of drug-coated stents may help to deliver high local doses of statins to enhance their effectiveness in the treatment of post-angioplasty restenosis.