[Mechanisms of action of statins and their pleiotropic effects]

This brief review and update considers a few aspects of the mechanisms of action of statins, especially those related to some of the pleiotropic effects that have clinical relevance. The beneficial effect on endothelial dysfunction is a class effect that is related not only to the lowering of plasma LDL-cholesterol but also to a direct effect on nitric oxide (NO) production. It is an early and sustained effect, linked to oxidative processes, that deserves particular attention since endothelial dysfunction is intimately linked to atherogenesis. Awareness of the anti-inflammatory effect came about following the observation that statin administration in humans reduces markers of inflammation in the circulation. The importance of these observations is ascribable to the fact that atherosclerosis is an inflammatory disease, that the inflammatory process in a coronary artery is now measurable in vivo in humans, that it contributes to the progression and the destabilization of the plaque, and also, because statins exert a number of effects that tend to stabilize it. Statins, and particularly lipophilic statins, in general inhibit cell proliferation, seemingly by multifaceted mechanisms. These include inhibition of cell cycle progression, induction of apoptosis, reduction of cyclooxygenase-2 activity and an enhancement of angiogenesis. At the center of these mechanisms stands the ability to inhibit G protein prenylation through a reduction of farnesylation and geranylgeranylation. This effect has been used to show that statins are anticarcinogenic in vitro and in animals. The clinical relevance of such a property remains to be proven but is supported by promising observations in animals and in humans which are detailed in this review. Finally, the ability of lipophilic statins to increase the production of bone morphogenetic protein-2 (BMP-2), and to enhance osteogenesis in animals combined with the results of several clinical studies should stimulate physicians to seriously consider an eventual indication of statins for the treatment of osteoporosis.