Unraveling pleiotropic effects of statins on plaque rupture.

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Several large-scale clinical trials have conclusively shown that statins markedly reduce clinical endpoints of atherosclerosis.1 A plethora of studies has also reported effects of statins other than cholesterol-lowering.2 These include effects on endothelial function, such as NO generation and NO-mediated vascular relaxation, the recruitment of monocytes and T cells into the arterial intima, their subsequent activation and expression of proinflammatory factors, the proliferation of vascular smooth muscle cells (VSMCs), and other events that result in arterial remodeling (Table). However, to date only a minority of these “pleiotropic” effects of statins have been demonstrated to be truly cholesterol-independent, ie, reversible by geranylgeranyl-pyrophosphate (GGPP), but not by cholesterol. (GGPP and cholesterol represent separate branches of the mevanolate pathway downstream of the step blocked by HMG-CoA reductase inhibitors.) For example, the elegant work of Liao and colleagues3 established that the modulation of NO is due to the inhibition of GGPP that in turn affects the bioavailability of regulatory proteins, such as Ras and Rho. It has also been established that statins may inhibit atherogenesis by reducing the formation of superoxide and other oxygen radicals that modulate many intracellular signaling pathways.4 Finally, statins may affect the consequences of plaque rupture by modulating thrombosis and fibrinolysis. In fact, statins decrease the expression of tissue factor in lesions, reduce platelet activation, and improve fibrinolytic activity through preservation of endothelial function, but it is unclear whether these effects are common to the entire class of statins, because some compounds seem to exert opposite effects.5 Despite the increasing evidence obtained in vitro and in experimental models, the clinical relevance of pleiotropic effects of statins is still debated.6 View this table: Table 1. Pleiotropic Effect of Statins Potentially Affecting Plaque Rupture: Current Evidence for Their In Vivo Occurrence See page 1832 The question whether specific pleiotropic effects contribute …