Over the past decade, cell culture and animal studies have provided convincing evidence for cholesterol-independent effects of statins. It is believed that some or all of these pleiotropic effects may contribute to the reduction in cardiovascular risks with statin therapy. These effects include, but are not limited to: improvement in endothelial function through upregulation of NO synthesis and bioavailability or decrease in endothelin-1 expression; reduction in vascular inflammation through inhibition of macrophage activation, proliferation, and secretion of matrix metalloproteinases; inhibition of vascular smooth muscle proliferation and platelet activation; enhancement of the fibrinolytic system through induction of tissue-type plasminogen activator (t-PA) and downregulation of plasminogen activator-1 (PAI-1) expression; and promotion of neovascularization through direct angiogenesis or mobilization of endothelial progenitor cells (EPCs) 1–5 (Fig. 1). In addition, statins have been shown to exert antioxidant effect through downregulation of AT1R expression and inhibition of NADPH oxidase activity 6;7. Some of these antioxidant effects of statins may contribute to their beneficial effects on myocardial hypertrophy, fibrosis, and possibly, heart failure 8;9.

The biological mechanism underlying most of these pleiotropic effects of statins is inhibition of isoprenoid metabolism in non-hepatic cells (Table 1). Inhibition of mevalonate synthesis reduces cholesterol synthesis as well as synthesis of the isoprenoid intermediates of the cholesterol synthesis pathway, such as farnesol and geranylgeraniol 10. Isoprenoids are necessary for the posttranslational modification and subsequent trafficking of intracellular signalling molecules. In experimental systems, inhibition of isoprenylation of Rho GTPases mediates some of the cholesterol-independent effects of statins 11 (Fig. 2). For example, the RhoA-dependent cytoskeleton is a negative regulator of eNOS mRNA stability, and statins upregulate eNOS expression by inhibition of RhoA geranylgeranylation 12. Hence, is it is now possible to explain some important downstream effects of HMG CoA reduction at a cellular level and how they modify cellular phenotype through non-lipid-dependent mechanisms. In addition, many of these effects can be experimentally reproduced in much shorter time course than would be expected by effects mediated by lipid lowering alone. However, the question remains, do these effects occur in humans - and are they quantitatively relevant?